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Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

Nicholas A. Meanwell*
Nicholas A. Meanwell
Discovery Chemistry and Molecular Technologies Bristol-Myers Squibb Research and Development P.O. Box 4000, Princeton, New Jersey 08543-4000, United States
*Phone: (609) 252-6195. E-mail: [email protected]
More by Nicholas A. Meanwell
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http://orcid.org/0000-0002-8857-1515

Cite this: J. Med. Chem. 2018, 61, 14, 5822–5880

Publication Date (Web):February 5, 2018

https://doi.org/10.1021/acs.jmedchem.7b01788

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Abstract

The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

Introduction

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The design of bioisosteres is a useful principle in drug design that, although widely practiced, is contextual in application. Thus, the design of bioisosteres requires detailed insight into the physicochemical properties of an element, heterocycle, or functional group if effective emulation is to be achieved and, ideally, complemented by a similar level of understanding of the binding site of a molecule.(1) Bioisosterism has its origins in the concept of isosterism between relatively simple functionality and small molecules that was advanced by Moir and Langmuir a century ago.(1) However, contemporary interpretations of structural metaphors in a biological setting accommodate a much broader range of bioisosteric structural motifs that can vary considerably in size and shape from the functionality being emulated.(1,2) Thus, modern bioisosteric relationships are rooted far more in functional reproduction of biochemical pharmacological properties that reflect aspects of molecular recognition that are often unique to a specific environment.(1) Consequently, the relationship between shape and/or aspects of physicochemical properties of a bioisostere can be oblique. Fluorine has played a prominent role in drug design since the approval of the first fluorinated drug, the synthetic 9α-fluoro-substituted corticosteroid fludrocortisone (1), on August 18, 1955.(3) The applications of fluorine in the design of drugs and agricultural chemicals continues to grow as our knowledge and understanding of how to take full advantage of the unique properties of this element matures.(4−6) This has been fostered by the development of innovative synthetic methodology which is providing access to new fluorinated motifs with interesting topographies and physicochemical attributes.(7) While early applications of fluorine as a bioisostere focused on the relatively simple replacement of hydrogen atoms in drug molecules, often as a means of influencing metabolism, the last 20 years has seen broader deployment of fluorine and fluorinated motifs in the construction of more sophisticated structural arrangements that are able to emulate and influence a number of more traditional functionalities. In this Perspective, I provide a synopsis of some of the practical applications of fluorine as a bioisostere in drug design, ranging from the simple substitution of the hydrogen atom in the setting of alkyl and aromatic moieties to examples that utilize fluorine in conjunction with additional functionalities to explore bioisosteric relationships that are more esoteric in nature and which are, in some cases, less well developed.

Key Properties of Fluorine of Relevance to Bioisostere Design

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The effective application of fluorine in drug design requires an understanding of its key physicochemical properties, and those of relevance to the design of bioisosteres are summarized in Table 1.(4,8) Fluorine is approximately 20% larger than hydrogen based on comparison of the van der Waals radii, while the length and size of a C–F bond is more closely aligned with a C═O bond than either the shorter C–H or longer C–OH, C–C≡N, or S═O bonds. The electronegativity of fluorine is closer to that of oxygen, which is reflected in the dipole moment of the C–F bond being larger and in the opposite direction of a C–H but less than that of C═O, S═O, C–OH, and C–C≡N moieties. Fluorine is modestly more lipophilic than a hydrogen atom and significantly more lipophilic than OH, C═O, C≡N, or sulfoxide and sulfone substituents. Unlike chlorine, bromine, and iodine, fluorine does not engage in halogen bonding and is nonpolarizable, a property that underlies strong electrostatic interactions which can be attractive or repulsive.(4) These properties confer fluorine with considerable versatility such that it has been explored as a potential bioisostere of the hydrogen atom, carbonyl and sulfonyl functionalities, the carbinol moiety, and the nitrile, with effective functional mimicry very much dependent upon the biochemical context.

Table 1. Key Properties of the C–F Bond Compared to the C–H, C═O, C–OH, C–C≡N, and S═O Bonds

bond	bond length (Å)	van der Waals radius (Å)	van der Waals volume of atom (Å³)	total size (Å³)	electronegativity of the element	dipole moment μ (D)	π	bond dissociation energy (kcal/mol)
C–H	1.09	1.20	7.24	2.29	2.20	∼−0.4	0	98.8
C–F	1.35	1.47	13.31	2.82	3.98	1.41	0.14	105.4
C–Cl	1.77	1.75	22.45		3.16	1.87 (CH₃Cl)	0.71	78.5
C═O	1.23	1.52	14.71	2.73	3.44	2.33 (H₂C═O)	CHO: −0.65	85 (π bond)
C–OH	1.43 (CH₃OH)	1.52	14.71		3.44	2.87 (CH₃OH)	–0.67	84.0
	1.48 (CH₃ CH₂OH)					1.66 (CH₃ CH₂OH)
C–C≡N	2.22 (HCN)					3.92 (CH₃CN)	–0.57
S═O	1.44 (CH₃SO₂ CH₃)	1.52	14.71		3.44	4.44 (CH₃SO₂ CH₃)(9)	CH₃SO: −1.58
							CH₃SO₂: −1.63

Fluorine as a Bioisostere of the Hydrogen Atom in Alkyl Moieties

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Developability Aspects Associated with Fluorination and the Size of the CF₃ Moiety

Replacing hydrogen atoms with fluorine has been explored extensively in drug design, most commonly to replace those bound to an aromatic ring or in the context of a CF₃ for CH₃ replacement where these substitutions can modulate potency or interfere with metabolic modification.(10) The replacement of a hydrogen atom by fluorine would be expected to add to the physical size, modestly increase the lipophilicity of a molecule based on the π coefficient of 0.14 determined for fluorine, but more significantly increase molecular weight (MW) (Table 1). Thus, the replacement of a CH₃ by CF₃ would be expected to increase the overall lipophilicity of a molecule (cLog P) by 0.42 and add 54 Da to the MW, parameters that would be anticipated to negatively affect ligand efficiency metrics.(11) However, fluorination of a molecule does not necessarily lead to an increase in lipophilicity, and several structural motifs are associated with increased polarity based on a matched molecular pairs (MMP) analyses.(4d,12) Fluorine atoms that are deployed in a molecule such that they are proximal to an oxygen atom, separated by a distance of <3.1 Å, can exhibit a lower measured Log P value, while vicinal alkyl fluorides offer increased polarity as a function of C–F dipole alignment that is favored by the gauche effect, stabilizing a more polar conformation (vide infra). Adding to these observations, concerns around the effect of fluorination on ligand efficiency metrics has been addressed by a careful MMP analysis of the performance of a large data set of compounds evaluated in in vitro developability assays.(13) This study, in which fluorine was present in a range of environments but most commonly incorporated as an aryl-F, aryl-CF₃, or an aryl-CF₂H motif, concluded that polyfluorination may not necessarily represent a deleterious modification. On the basis of an analysis of P-glycoprotein (P-gp) recognition, lipophilicity, metabolic stability, and membrane permeability using assays conducted in vitro, fluorine was found to behave more like a hydrogen atom, leading to the contention that up to five fluorine atoms can be introduced into a molecule without a significant impact on performance in these assays.(13) As a consequence, it was suggested that the MW increase associated with the introduction of fluorine may be ignored in efficiency metric calculations and that the fluorine-corrected molecular weight MW_FC (MW_FC = total MW – MW of the fluorine atoms present in the molecule) should be used as a more suitable and relevant descriptor for this purpose.(13)

The size of the CF₃ moiety has also been somewhat challenging to definitively assess and this moiety has often been considered to be isosteric with an iso-propyl substituent, although it is clearly of a different shape.(4g) The calculated van der Waals volumes, the A values, and both experimental measures of biphenyl rotational interference compiled in Table 2 all indicate that the CF₃ is a smaller than an iso-propyl substituent with the exception of the Taft Es value which uniquely indicates the reverse, although the differences projected by several of these measurements are relatively modest.(14,15) Under some circumstances, the CF₃ moiety has been found to sterically dominate a phenyl or tert-butyl substituent in defining the stereochemical outcome of an aldol reaction.(15d−f) Assessing the size of the CF₃ moiety in biochemical applications is unlikely to simplify the inherent complexity associated with this question given the context-dependent nature of drug–target interactions. Nevertheless, an experiment designed to compare the size of the CF₃ and an iso-propyl substituent in a biological context has been conducted with matrix metalloprotease-9 inhibitors where the alkyl side chains of 2 and 3 project into the well-defined lipophilic S1′ pocket of the enzyme.(16) In both series, an alkyl chain terminating in CH₃ or CH₃CH₂ was associated with potent inhibitory activity, while the respective iso-propyl homologues were over 1000-fold weaker; however, the two CF₃-substituted derivatives largely retained the potency of the smaller alkyl groups, data captured in Table 2. These results indicate that, in this specific context, the CF₃ moiety could be considered to be bioisosteric with an ethyl rather than an iso-propyl substituent.(16)

Table 2. Comparisons of the Size of Alkyl and CF₃ Groups Based on Van Der Waals Volume, A Values, Taft Es Values, Biphenyl Interference Values, and the Activity of the Two Structurally-Related Series of MMP-9 Inhibitor Probes 2 and 3

	vdW volume (Å³)	A value (kcal/mol)	Taft Es value	biphenyl rotational interference value (kcal/mol)(14)	experimental biphenyl rotational B value (ΔG^⧧_rot, kcal/mol)(15)	inhibition of MMP-9 by 2/3 IC₅₀ (nM)(16)
H	1.20		0
F	13.3	0.15	–0.46	4.6	4.4
Me	21.6	1.70	–1.24	9.7	7.4	1/10
Et	38.9	1.70	–1.31		8.7	2/27
CF₃	39.8	2.10	–2.40	12.1	10.5	87/22
iPr	56.2	2.15	–1.71	12.6	11.1	1800/4500
tBu		>4.50	–2.78	18.3	15.4

Fluorination as an Approach to Reducing Metabolism

Because the introduction of fluorine can lead to resistance toward oxidative metabolism, fluorination has developed into a popular approach to addressing the poor pharmacokinetic performance of compounds in vitro and in vivo.(10,17) Under some circumstances, a CH₃ substituent can be replaced directly by a fluorine atom despite being 40–50% smaller, although metabolically labile alkyl groups are more commonly addressed by more sophisticated motifs in which the CF₃ moiety plays a prominent role. While the introduction of fluorine is often directed specifically toward a metabolic soft spot, the effects of fluorination can be indirect and complex. As a consequence, the effect can range from negative or null, possibly due to redirecting metabolism to an alternative site, to global protection toward metabolic modification, while the effects exerted on the metabolic stability of proximal functionality can be positive or negative dependent upon context.(18−20)

Examples where replacing hydrogen atoms with fluorine exerts a positive effect on metabolism are provided by the taxoids 4 and 5, which are related to paclitaxel (6) and the GPR119 agonists 7 and 8.(21,22) For the taxoid derivatives, CYP 3A4 oxidation of the C-3′ iso-butenyl CH₃ groups of 4 represented an important metabolic pathway that prompted replacement of the allylic methyl substituents by fluorine, affording 5. Fluorinated derivative 5 exhibited highly potent cytotoxicity toward a series of human cancer cell lines, with a 10–1000-fold advantage over 6.(21) Remarkably, 5 was quite resistant to metabolic modification in the presence of CYP 450 enzymes, with the introduction of the two fluorine atoms providing protection against metabolic modification at the C-3′ N-t-Boc and C-6 methylene moieties known to be the major sites of metabolic lability in the homologue 6.(21)

In the example provided by GPR119 agonists, compound 7 displayed poor metabolic stability in vitro which was attributed to its high lipophilicity, ELog D = 4.3.(22) Replacing of the CH₃ substituent β- to the amide N atom with fluorine afforded 8, which exhibited enhanced metabolic stability while also illuminating aspects of the bound conformation. This was the result of the N-β-fluoroethylamide adopting a preferred conformation in which the two elements were in a gauche relationship (vide infra), which constituted about 75% of the conformer population on the NMR time scale.(22)

In a study seeking replacements for a tert-butyl moiety that would offer improved metabolic stability, systematic modifications to the 3 methyl groups were explored in the context of the simple biphenyl derivative 6-(4-(tert-butyl)phenyl)nicotinonitrile (9) (Table 3).(23,24) The effects of structural modification were compared with compound persistence when incubated in rat and human liver microsomes (RLM and HLM), respectively, with the results summarized in Table 3. While some success was achieved with the polar substituents found in 10–13, these were viewed as potential liabilities in the context of a drug target where the tert-butyl group may be accommodated in a hydrophobic binding pocket. The CF₃-susbstitued cyclopropyl (Cp-CF₃) moiety exemplified in 17 emerged as the optimal lipophilic substituent, with higher metabolic stability in both RLM and HLM preparations than 14–16.

Table 3. RLM and HLM Half-Life Values Associated with a Series of 6-(4-Substituted-phenyl) Nicotinonitrile Derivatives 9–17

To further demonstrate the utility of the Cp-CF₃ substituent, comparison of liver microsomal stability data for six matched pairs of biphenyl amide derivatives was probed, where the outcome was a positive result in each case, and as a replacement for the metabolically labile tert-butyl moiety in the steroid 5α-reductase inhibitor finasteride (18).(24) The Cp-CF₃ analogue 19 exhibited a t_1/2 in HLM of 114 min which compared to 63 min for 18, with recognition that in this particular example, the modification may not protect against metabolism at other sites of the molecule and may cause a redirection of metabolism to alternative sites.

The Cp-CF₃ moiety featured prominently in a complementary study in which a series of tert-butyl isosteres were the subject of detailed in vitro profiling when installed in the background of the dual endothelin A and B antagonist bosentan (20) and the CCR-9 antagonist vercirnon (21), both of which contain a 4-(tert-butyl)benzenesulfonamide moiety.(25) In this analysis, the profiles of the tert-butyl progenitors were compared with the Cp-CF₃, CF₃, SF₅, and [1.1.1]-bicyclopentane (BCP) homologues, with the calculated relative sizes of these substituents compiled in Table 4. With the exception of Cp-CF₃, all of the substituents are smaller than a tert-butyl, and Log D measurements indicated that lipophilicity increased in the order of CF₃ < SF₅ < Cp-CF₃ < tBu < BCP while the pK_a of the sulfonamide N–H increased in the order of SF₅ < CF₃ < Cp-CF₃ < tBu ≈ BCP.

Table 4. Calculated Volumes of a Series of Substituents Normalized to the tert-Butyl Moiety

In the context of 20, the Cp-CF₃- and BCP-substituted analogues performed similarly to the parent molecule as antagonists at the endothelin A and B receptors, while the CF₃- and SF₅-substituted derivatives were 10-fold less potent.(25) When incorporated as tert-butyl replacements in 21, all of the substituents performed similarly to the prototype in a CCR9 functional assay. In both series of compounds, there was a trend toward enhanced metabolic stability in liver microsomes for these substituents compared to the tert-butyl-substituted prototypes, with CF₃ and SF₅ the most effective. No significant CYP inhibitory effects were observed with either series, but the effects on solubility were varied in analogues of 20 while all of the modifications led to reduced solubility in the context of 21.

These general observations have support from examples harvested from studies conducted across a range of compound structures with widely varying biochemical mechanisms, although there are unique contextual variations in individual performance. For example, the FMS-like tyrosine kinase 3 (FLT3) inhibitor quizartinib (22), which is in phase 3 clinical trials for the treatment of acute myeloid leukemia (AML), is metabolized at the tert-butyl moiety in humans to afford alcohol 23.(26,27) This lability was addressed in a related series of compounds by replacing the tert-butyl substituent with Cp-CF₃, with 24 characterized as a potent FLT3 inhibitor, K_d = 0.6 nM, with improved metabolic stability compared to its tert-butyl progenitor.(28)

The Cp-CF₃ moiety in the human bombesin receptor subtype-3 (hBRS-3) agonist 26 provided a partial solution to the high metabolic turnover rate observed with the prototype 25, with further refinement of the carbinol CH₃ to a CF₃ affording the more advanced compound MK-5046 (27).(29)

The 1,1,1-trifluoro-2-methylpropan-2-yl moiety addressed the metabolic lability of the tert-butyl substituent of the selective phosphatidylinositol-3 kinase-α (PI3Kα) inhibitor 28, a precursor to alpelisib (NVP-BYL719, 29) which is currently in phase 3 clinical trials for the treatment of breast cancer (Table 5).(30) The main metabolic pathways for 28 were determined to be hydroxylation of one of the CH₃ moieties of the tert-butyl element and hydrolysis of the primary amide. The design of 29 was inspired by an examination of an X-ray cocrystal structure which indicated scope to slightly enlarge the size of tert-butyl moiety in order to more completely fill the pocket of the enzyme into which it projected. In the event, the CF₃ analogue not only retarded metabolism at this site, leading to lower clearance in vivo and excellent oral bioavailability (F = 106% in mouse, F = 58% in rat, and F = 140% in dog) but also enhanced potency by 2-fold. In the cocrystal structure of 28 with PI3Kα, one fluorine atom of the CF₃ moiety was described as engaging in a hydrogen-bonding interaction with the protonated amine of Lys₈₀₂, while the bound conformation of the inhibitor was stabilized by an intramolecular interaction between one of the lone pairs of electrons on the urea oxygen atom and the low lying C–S σ* of the sulfur atom of the thiazole, interactions depicted in Figure 1.(30,31)

Table 5. SARs, Metabolic Stability, and in Vivo Clearance Associated with the PI3Kα Inhibitors 28 and 29

	R	P110α IC₅₀ (nM)	P110β IC₅₀ (nM)	P110δ IC₅₀ (nM)	P110γ IC₅₀ (nM)	RLM clearance (μL/min/mg)	rat clearance in vivo (mL/min/kg)
28	CH₃	14	4400	330	430	77	39
29	CF₃	5	1200	290	250	29	10

Figure 1. Key drug–target interactions between 29 and the PI3Kα enzyme and conformational bias provided by an intramolecular O to S interaction.

Similarly, in a series of inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) that led to the discovery of CEP-32496 (30), the 1,1,1-trifluoro-2-methylpropan-2-yl substituent was a more effective bioisostere of a tert-butyl substituent that adequately addressed the metabolic lability associated with the prototype, preserving potency in this example more effectively than a Cp-CF₃ substituent which was a 2-fold weaker enzyme inhibitor.(32)

In a series of γ-secretase modulators based on the tert-butyl-substituted lead compound 31, which combined modest potency with poor metabolic stability, substituting one of the CH₃ moieties with a CF₃ gave 32, which significantly improved both parameters (Table 6).(33) This result allowed further refinement of the structure by pruning of the substituent which revealed that both potency and metabolic stability were dependent upon the absolute configuration of the trifluoroethyl moiety. The (R)-isomer 33 was found to be superior to the (S)-antipode 34 and it was this motif that was retained in the optimized molecule 35 where the addition of a CH₃ moiety to the linker element was found to improve potency by a further 3-fold. More recently the CF₃ oxetane was evaluated as a tert-butyl replacement in the context of 36, a modification that retained biological potency while lowering E Log P, enhancing LipE, and improving metabolic stability in HLM compared to 31.(34)

Table 6. SARs, Lipophilicity, and Metabolic Stability Associated with a Series of γ-Secretase Modulators 31–36a

^{^a}

*LipE = pIC₅₀ – Log P.

The triazole-based CF₃ substituent in sitagliptin (40), a potent dipeptidyl peptidase-4 (DPP-4) inhibitor marketed for the treatment of type 2 diabetes, is an important determinant of both its in vitro and in vivo profile.(35) In this example, the CF₂H (38) and CF₃ (40) moieties performed more effectively as bioisosteres of the CH₃ in prototype 37, while the CF₂CF₃ substituent in 39 resulted in 2-fold lower enzyme inhibitory potency (Table 7). Strikingly, while the oral bioavailability of each of the 3 fluorinated 38–40 derivatives in the rat was significantly improved compared to 37, this was not the result of significant changes in clearance in vivo.

Table 7. SAR, Metabolic Stability, and Oral Bioavailability of the Series of DPP-4 Inhibitors 37–40

	R	DPP-4 IC₅₀ (nM)	rat clearance (mL/min/kg)	oral bioavailability (F, %)a
37	CH₂CH₃	37	70	2
38	CF₂H	29	66	39
39	CF₂CF₃	71	58	61
40	CF₃	18	60	76

^{^a}

Dose = 1 mg/kg IV; 2 mg/kg PO.

Fluorination of the terminal CH₃ groups of the γ-secretase inhibitor 41 was examined as an approach to address the metabolic modification that had been determined to occur at this site.(36) By replacing the CH₃ groups with CF₃, intrinsic enzyme inhibitory activity was improved marginally from an IC₅₀ value of 25 nM for 41 to 16 nM for begacestat (42), while the t_1/2 in RLM increased from 1 to 8 min. This effect extended to mouse LM, where the t_1/2 increased from 2 to 24 min, but not to HLM, where the measured t_1/2 values for 41 and 42 were comparable at 8 min. The improved metabolic stability in mouse LM translated to enhanced exposure and better efficacy at lowering Aβ₄₂ levels in mice in vivo, leading to 42 being selected for clinical evaluation.

Fluorination of amide-bound alkyl groups has been shown to interfere with oxidative N-dealkylation processes.(37,38) For example, replacing the iso-butyl amide substituent of the tetrahydroisoquinolone-based antimalarial agent 43 with the trifluoroethyl moiety found in 44 resulted in only a modest reduction in cell-based potency while metabolic stability in mouse LM was substantially increased.(37) Similarly, the CF₃CH₂ substituent in the slowly activating cardiac delayed rectifier potassium current (I_Ks) inhibitor 46 (L-768,673) was designed to interfere with the N-dealkylation observed with the N-methyl analogue 45, a known metabolic pathway for benzodiazepine derivatives, and this compound exhibited long lasting effects on the QT interval in dogs in vivo.(38)

The heptafluoroisopropyl substituent was originally explored in the agricultural chemistry arena and is found in the pesticides flubendiamide (47), which activates insect ryanodine (Ry)-sensitive intracellular Ca²⁺ release channels, and broflanilide (48), a noncompetitive insect γ-aminobutyric acid (GABA) receptor antagonist.(39) This moiety has also found application in drug design campaigns where it has been evaluated as a substitute for the iso-propyl and tert-butyl substituents, most notably in the context of the hypocholesterolemic steroid 50 and the bosentan analogue 51, both of which offer improved metabolic stability compared to their progenitors 49 and 20, respectively.(40,41) While 50 demonstrated higher potency toward lowering serum cholesterol levels in rats in vivo following oral dosing, 51 bound to the ET_A receptor with 16-fold reduced affinity (IC₅₀ = 75.4 nM) compared to 20 (IC₅₀ = 4.7 nM) although the selectively index over the ET_A receptor was enhanced.

The selective aspartate semialdehyde dehydrogenase inhibitor 53 offers enzyme inhibitory potency comparable to the tert-butyl derivative 52, while substitution of the iso-propyl moiety in the hypoglycemic agent 54 with either tert-butyl (54) or heptafluoroisopropyl (56) led to reduced effects on sugar levels in vivo.(42,43)

In a series of inhibitors of aryl urea-based soluble epoxide hydrolase (SEH) inhibitors, fluorination of the phenyl substituent group conferred increased potency with the CF₃ (59) and CF₃O (60) analogues 3- and 6-fold more potent than the iso-propyl (57) and tert-butyl (58) prototypes, respectively (Table 8).(44) However, the heptafluorisopropyl substituent in 61 provided a uniquely potent inhibitor, with an almost 20-fold advantage over 59 and 60. Interestingly, while the aqueous solubility of 61 was 15-fold lower than 59, the CF₃O-substituted derivative 60 was 8-fold more soluble than both 57 and 59, an observation not anticipated by the predicted lipophilicity values.

Table 8. Structure and Inhibitory Potency of a Series of Soluble Epoxide Hydrolase (SEH) Inhibitors

	R	SEH IC₅₀ (nM)	solubility (μg/mL)
57	iPr	1.17	2.60
58	tBu	2.44	0.02
59	CF₃	0.37	2.60
60	CF₃O	0.36	22.5
61	(CF₃)₂CF	0.02	0.17

One word of caution with respect to the taking advantage of the heptafluoroisopropyl moiety as an aromatic substituent is the potential for it to exist as atropisomers when there is a large ortho- substituent. This has been observed with 62, where the ¹H NMR spectrum indicated a 60:40 ratio of rotamers, with 62a identified as the major component (Figure 2).(45) The coalescence temperature, as determined from monitoring the C-6 proton in Cl₂DCCDCl₂, was 108 °C, corresponding to an energy barrier of 19.4 kcal/mol. A similar observation was made with the naphthalene and benzofuran analogues in which the pyrazole ring of 62 is replaced by benzene and furan, respectively.

Figure 2. Atropoisomerism associated with 4-(perfluoropropan-2-yl)-1H-indazol-5-amine.

The strategic deployment of a fluorine atom can exert an effect on drug metabolism and toxicity in a less direct fashion, as exemplified by the design of the fluoro analogue 64 of the anticonvulsant felbamate (63).(46) Clinical use of 63 is associated with aplastic anemia and hepatotoxicity that is idiosyncratic in frequency and which has been suggested to be due to metabolic release of atropaldehyde (66), a bivalent electrophile capable of cross-linking proteins.(46,47) The mechanism of release of 66 is postulated to occur by the metabolic process depicted in Scheme 1 and is believed to be the consequence of an irreversible retro-Michael reaction that results in the elimination of H₂O and CO₂ from 65. The formation of 66 is efficiently blocked by the fluorine atom present in 64, which prevents the fluorinated metabolite analogous 65 from undergoing the retro-Michael reaction.(47) The preclinical anticonvulsant profile of 64 compares favorably to 63 and is, in some circumstances, superior, and this compound has been advanced into clinical trials.(48,49)

Scheme 1. Metabolism of 63 and the Release of 66

Metabolic Activation of Fluoro-alkyl Derivatives

Despite the high strength of the C–F bond (Table 1) and the relatively poor ability of fluoride to act as a leaving group, circumstances have been documented where an alkyl fluoride derivative undergoes metabolic activation that sets the stage for the elimination of HF from sp³-hybridized carbon centers.(8,50) Fluorine atoms are introduced into the ring of pyrrolidine derivatives as an isostere of hydrogen designed to interfere with metabolism, moderate the basicity of the nitrogen atom if so configured, or modulate ring conformation (vide infra). However, one circumstance where this structural configuration presented problems is exemplified by the DPP-IV inhibitor 67, which was observed to generate protein adducts when incubated in RLMs.(50) The protein covalent binding associated with 67 was irreversible and dependent on both time and NADPH but could be abrogated by including GSH or N-acetyl cysteine in the incubation medium. Trapping experiments using semicarbazide, a hard nucleophile that reacts with aldehydes, helped to elucidate the metabolic pathway depicted in Scheme 2. Metabolic activation is believed to be initiated by α-hydroxylation adjacent to the nitrogen atom of the pyrrolidine ring to give the hemiaminal 68 that, upon ring opening to the aldehyde 69, is configured for the elimination of HF to form the Michael acceptor 70. The unsaturated aldehyde 70 is an electrophile with dual sites of reactivity and thus has the potential to cause protein cross-linking. However, the addition of a soft nucleophile like GSH would provide 71, which is presumably in equilibrium with the ring closed form 72.

Scheme 2. Metabolic Activation Pathway Deduced for the DPP-4 Inhibitor 67

Although this example provides a cautionary note with respect to the bioisosteric replacement of hydrogen by fluorine in pyrrolidine and, presumably, the homologous piperidine rings, detailed studies with the difluorinated pyrrolidine-based DPP-IV inhibitors 73 and 74 have indicated that for these molecules, this specific metabolic pathway is not followed.(51) The HIV-1 non-nucleoside reverse transcriptase inhibitor 75 exhibits a short life in RLM and HLM, and while the difluoro-pyrrolidine ring was determined to be the site of metabolism by an undetermined pathway, there was no apparent indication of reactive metabolite formation.(52)

2,2-Difluoro-1,3-benzodioxole Derivatives

The 1,3-benzodioxole moiety is a structural element in prevalent natural products found, for example, in the papaverine alkaloids, camptothecins, and several constituents of kava-kava.(53) However, this functionality is susceptible to metabolism by CYP 450 enzymes following a pathway that leads to the formation of a carbene intermediate that binds tightly to the Fe atom of the enzyme (Scheme 3). This carbene-bound intermediate is referred to as a metabolite intermediate (MI) complex that inactivates the enzyme until the complex degrades, which relieves the inhibition, with the methylenedioxy carbon atom released as carbon monoxide.(54,55) However, this step generates a catechol that can be subject to bioactivation by oxidizing enzymes, including CYP 450s, to afford ortho-quinone derivatives that are highly reactive toward both soft and hard nucleophiles.(55,56) Consequently, the benzo[d][1,3]dioxole element is considered to be a structural alert because it can be associated with drug–drug interactions, metabolic activation, and toxicities that includes hepatotoxicity.(55) For example, despite its relatively low clinical dose of 10–50 mg, the antidepressant paroxetine (76) is metabolized by CYP 2D6 in a fashion that leads to inhibition of the enzyme, inhibiting both its own metabolism and that of other drugs that are cleared by CYP 2D6.(57)

Scheme 3. Cytochrome P450-Mediated Metabolism of the 1,3-Benzodioxole Moiety to a MI Complex

An appreciation of these problems has prompted the design of 1,3-benzodioxole replacements that would abrogate this metabolic pathway while preserving the physicochemical properties requisite for biological activity.(58) Deuteration of the methylene moiety represents the most conservative isosteric substitution that can slow this metabolic process while preserving biological activity and has been successful in the context of CPT-347 (77), a deuterated derivative of 76.(59) However, fluorination offers a more definitive solution, although the effects on biological potency are less predictable with increases, decreases and minimal changes described that show dependence on the specific target or chemotype within a target.(4,60−66) The fluorinated camptothecin analogue 78 was specifically designed to increase metabolic stability over the hydrogen-substituted prototype, a structural modification that resulted in improved exposure following oral administration of the compound as its prodrug 79.(60) Lumacaftor (VX-809, 80), which improves trafficking of the cystic fibrosis transmembrane regulator (CFTR) ΔF508 mutant and has been approved by the FDA for the treatment of cystic fibrosis, is a CYP inducer rather than an inhibitor and subject to limited metabolism, which involves oxidation and glucuronidation.(65) JNJ-42165279 (81) is a clinically evaluated, mechanism-based inhibitor of fatty acid amide hydrolase (FAAH) for which the 2,2-difluorobenzo[d][1,3]dioxole heterocycle was observed to be metabolically stable.(66)

Fluorination of Alkyl Groups and Conformational Effects

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In this section, the effects of fluorinating alkyl moieties proximal to a range of functional groups that can lead to an influence on the conformation of a molecule are discussed.

Fluorine for Hydrogen in Alkyl Groups Proximal to Amines

The substitution of hydrogen attached to sp³ carbon atoms by fluorine can influence the properties of a molecule significantly in a fashion that is dependent upon the nature of proximal functionality. The gauche effect between fluorine and substituents on the adjacent carbon atom can be an effective approach to influencing the conformation of a molecule.(67) The calculated energetic preferences for the gauche conformation of a series of 2-substituted, 1-fluoroethane derivatives are compiled in Table 9, and this phenomenon has been taken advantage of to probe aspects of molecular recognition.(67) Thus, the conformations of 3-F GABA 83 and 84,(68) the 2,3-difluoro GABA analogues 85–88,(69) and 3-fluoro-N-methyl-d-aspartate (NMDA) derivatives 91 and 92(70) have been analyzed in order to illuminate aspects of the bound conformation of their progenitors 82 and 89, respectively, while the conformation of the GABA element in the macrocyclic heptapeptide unguisin A (93), which is isolated from the marine fungus Emericella unguis, has been probed by incorporating 85–88.(71) The design principle behind these studies relies upon a gauche interaction between fluorine and the ammonium moiety to favor a specific conformation that is used to probe cognate receptors and, in the case of GABA, recognition by the transaminase. For 2,3-difluoro GABA, a gauche interaction between the two fluorine atoms provides an additional element of stereocontrol in addition to the gauche preference of the fluorine/ammonium elements.

Table 9. Calculated Stabilization Energies Favoring a Gauche Relationship in 2-Substituted 1-Fluoroethane

	stabilization energy (kcal/mol)
F	0.5–1.0
OH	1.0–2.0
OAc	1.6
NHAc	1.8
NH₂	0.9–1.0
NH₃⁺	5.8

Fluorine was introduced at the 3-postion of GABA (82) and the individual enantiomers (R)-3-F-GABA (83) and (S)-3-F-GABA (83) evaluated as ligands for the GABA_A and GABA_C receptors.(68) Because the cloned GABA_A receptor failed to distinguish between 83 and 84, the extended conformation A depicted in Figure 3, in which the two key functionalities are in an antiperiplanar arrangement that is available to both enantiomers, was considered to represent the bound topology. However, both the GABA_C receptor and the transaminase favored 83, suggesting that conformer B depicted in Figure 3 is that recognized by these proteins because that topographical arrangement is a conformation disfavored by 84.(68) Evaluation of the difluoro homologues 85–88 revealed that 85 was a more potent ligand for the GABA_C receptor than either GABA_A or GABA_B, while 86 exhibited dual GABA_A/GABA_C binding.(69) Interestingly, while both 85 and 86 adopted an extended, zigzag conformation, they elicited very different effects at the GABA_C receptor, with 85 an agonist while 86 acted as an antagonist.

Figure 3. Preferred conformation of 82 at the GABA_A receptor (A) and the GABA_C receptor and the transaminase enzyme (B) deduced from an evaluation of 83 and 84.

The preferred conformations of 91 and 92, fluoro-substituted derivatives of NMDA (89) which acts as an agonist at a subset of receptors that recognize glutamic acid (90), were analyzed by ¹H- and ¹⁹F-NMR, which revealed that 91 adopted the conformation depicted in Figure 4.(70) However, the precise conformation of 92 could not be determined, although one conformation was ruled out and density functional theory (DFT) calculations suggested that of the other two conformations, the one reflecting the arrangement depicted in Figure 4 was not favored. The (2S,3S)-isomer 91 evoked currents at GluN2A and GluN2B receptors expressed in Xenopus laevis oocytes that were indicative of agonistic activity, while 92 was silent. As consequence, it was suggested that the active conformation is as depicted in Figure 4, a conclusion consistent with the conformation of 89 at the closely related GluN2D receptor in the cocrystal structure.(70)

Figure 4. Proposed active conformation of NMDA at the GluN2A and GluN2B receptors after analysis of 91 and 92.

Fluorine for Hydrogen in Alkyl Groups Proximal to Amides

The replacement of a hydrogen on a carbon atom β- to an amide nitrogen with fluorine can affect biological activity in a positive or negative fashion, a function of modulating conformational preferences due to the influence of a gauche effect between these substituents.(67) This is elegantly exemplified in the context of proline-containing ligands where fluorine is introduced at the C-4 position of the ring. N-Acetyl proline methyl ester (94) exhibits a preference for the C^γ-endo conformation (Figure 5A) that is reinforced by the introduction of a 4-(S)-fluoro substituent in 95 (Figure 5B), while the 4-(R)-fluoro derivative 96 favors the C^γ-exo conformer presented in Figure 5C.(72) The trans-(Z) topology of the amide moieties in 94–96 is also favored, attributed to a stabilizing interaction between the oxygen of the tertiary amide and the exocyclic C═O carbon atom. This phenomenon is viewed as the donation of electron density from the nonbonded electrons of the amide C═O to the π* orbital of the adjacent CO₂Me (or CO·NHR) substituent, which confers a detectable element of pyramidalization to the electron accepting C═O moiety (Figure 6).(73)

Figure 5. Conformational preferences of N-acetyl-proline methyl ester (94) (A), N-acetyl-4-(R)-fluoro-l-proline methyl ester (95) (B), and N-acetyl-4-(S)-fluoro-l-proline methyl ester (96) (C).

Figure 6. Acetamide conformation of 94 depicting an n → π* interaction.

The effect of C-4 fluorination of a pyrrolidine ring on biological activity has been illustrated in the context of both DPP-4 and fibroblast activation protein (FAP) inhibitors where in each case the proline moiety is installed at P₁ and the nitrile engages with the active site serine of the protease in a Pinner-type reaction to reversibly form a stable iminoether.(74,75) In the series of DPP-4 inhibitors 97–100, the cis-4-F-(S)-isomer 98 was 450-fold more potent than the trans-4-F-(R)-isomer 99, SAR points that cannot be attributed to a steric effect because the 4,4-difluoro homologue 100 fully retained the potent enzyme inhibitory activity of the prototype 97 (Table 10). The cis-(S)-4-fluoro substituent stabilizes the C^γ-endo pucker, while the trans-(R)-4-fluoro isomer stabilizes the C^γ-exo pucker (Figure 5), and it is this phenomenon that is believed to underlie the observed SARs. These observations were reproduced in the FAP inhibitors 102–104, where the effects of fluorination and the preferred absolute configuration are identical to those observed with 97 and 98 (Table 10).(75)

Table 10. SARs for the 4-Substituted Pyrrolidine-2-nitrile-Based Inhibitors of DPP-4 (97–100) and FAP (101–104)

However, the SARs for fluorination of a proline moiety installed at P₂ of the series of thrombin inhibitors 105–108 reflected the opposite preference to that observed with the P₁ moiety of DPP-4 and FAP inhibitors.(76) In this series, the trans-4-(R)-fluoro isomer 106 was 300-fold more potent than the cis-4-(S)-fluoro isomer 107, while the 4,4-dilfuoro analogue 108 was 6-fold less potent than the hydrogen prototype 105 (Table 11).

Table 11. SARs Associated with 4-Fluorination of the Inhibitors of Thrombin 105–108

	R	R′	thrombin K_i (nM)
105	H	H	0.6
106	F	H	0.37
107	H	F	110
108	F	F	3.6

The effects of fluorination of a proline ring do not always manifest as an influence on potency. In the series of VLA-4 antagonists 109–113, all three fluorinated compounds 111–112 exhibited potency comparable to the parent 109 and the 4-(R)-hydroxy derivative 110, indicative of considerable tolerance for substitution at this region of the pharmacophore.(77)

Fluorine for Hydrogen in Alkyl Groups Proximal to Fluorine

An understanding of the conformational preferences of alkanes in which hydrogen atoms have selectively been replaced by fluorine can confer advantageous effects that may be useful in drug design (Figure 7).(78−81) The C–C–C bond angle of the R–CF₂–R moiety widens to ∼118°, while the F–C–F angle is narrowed to ∼104° relative to normal tetrahedral carbon bond angles, which can manifest as a Thorpe–Ingold effect (Figure 7A).(78) When CF₂ moieties are introduced in a 1,4 relationship to an alkyl chain, dipole–dipole interactions and the relief of steric buttressing favors an extended conformation (Figure 7B). Vicinal difluoroalkanes adopt a gauche conformation that overrides the unfavorable C–F dipole–dipole alignment and, as a consequence, confers increased polarity to a molecule.(79,80) For 1,3-difluoroalkanes, the conformational preferences are dictated by favorable dipole–dipole alignment, with the preferred conformation depicted in Figure 7D estimated to be 3.3 kcal/mol lower in energy than that in which the C–F dipoles project in the same direction.

Figure 7. Geometry of 1,1-difluoroalkanes (A), the 1,4-di-CF₂ motif (B), and conformational preferences for 1,2-difluoro- (C) and 1,3-difluoro-alkanes (D).

The conformational effects of fluorination patterning have been examined in the stearic acid derivatives 114 and 115 and the substituted palmitic acids 116–118.(78) The higher melting point of the (±)-threo-isomer 115 (86–88 °C) compared to the (±)-erythro-configured 114 (67–69 °C) was attributed to the ability of 115 to adopt an elongated form stabilized by F–F gauche interactions that project the alkyl moieties in an antiperiplanar arrangement, thereby minimizing unfavorable steric interactions and facilitating improved crystal packing.(78b) In contrast, the two conformations of the (±)-erythro-isomer 114 that are stabilized by F–F gauche interactions also place the alkyl chains in a gauche relationship, while the conformation with the alkyl chains antiperiplanar sacrifices the F–F gauche effects. The melting point of 118 (89.9 °C) was higher than palmitic acid (62.5 °C) and 116 (62.9 °C), while 117 was isolated as an amorphous solid that could not be obtained in crystalline form.(78a) Single crystal X-ray structures of 116 and 118 revealed extended, zigzag-type conformations that presumably facilitate crystal packing, while the amorphous nature of 117 was attributed to repulsive intramolecular effects associated with the pattern of fluorination that lead to disorder.

An example of the application of fluorination patterning to conformational control is provided by a detailed analysis of the solid state and solution conformations of a series of trifluorinated 1,3-diphenylpropane derivatives.(80) Uniquely, the all-anti isomer 119 was found to adopt a conformation that placed the two aryl rings in a topography that mimicked those of the preferred conformation calculated for 2-benzyl-2,3-dihydrobenzofuran (120). This provides an interesting example of how isosterism at the level of atom replacements (F for H) can translate into potential higher order bioisosteric relationships.

The effects of the fluorination pattern of alkyl side chains on the physicochemical properties of a molecule has been evaluated in the structurally homologous 3-propyl-1H-indoles 121–126 and 3-butyl-1H-indole derivatives 127–129 compiled in Table 12.(81) The experimental results revealed interesting effects of the pattern of fluorine substitution in the propyl series 121–126, with the vicinal difluoro derivative 125 less lipophilic than its geminal difluoro isomer 123, reflected in the lower measured value of Log P. These properties translated into a more than 8-fold increase in aqueous solubility compared to the parent alkane 121 despite the addition of the two slightly more lipophilic fluorine atoms (Table 12). This result was attributed to the gauche interaction between the two fluorine atoms of 125 favoring a conformation that projects the C–F dipoles in a similar direction, reflected in the higher dipole moment of 1.63 D compared to 1.16 D for the geminal arrangement in 123. For the butyl series 127–129, the vicinal difluoro-substituted compound 129 was less lipophilic than the geminal-substituted analogues 127 and 128, which translated into modestly higher aqueous solubility. Indeed, the Log P value measured for 129 was only slightly higher than that for the vicinally substituted homologue 125 despite the presence of the additional CH₂ moiety, providing some instruction on how to deploy fluorine to advantageously modulate physical properties. The metabolic stability of the compounds in liver microsomal preparations was also evaluated, and while there appeared to be some enhancement associated with increased fluorination, the results were less than definitive.(81)

Table 12. Physicochemical Data Associated with the Series Fluorinated 3-Alkyl Indole Derivatives 121–129

A practical consequence of the effect of a considered deployment of fluorine patterning on the solubility of a compound can be appreciated by comparing the properties of the homologous Mycobacterium tuberculosis (Mtb) inhibitors 130 and 131.(82) While both compounds are effective Mtb inhibitors that act by an unknown mechanism, the aqueous solubility of the CF₂H-substituted compound 131 was more than 20-fold higher than the CF₃ homologue 130 despite a modest increase in the measured value of Log P.

Replacing Hydrogen by Fluorine in Aromatic Rings

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Aryl Fluoride Derivatives and Metabolism

The judicious substitution of a hydrogen atom in aromatic and heteroaromatic rings by a fluorine atom can exert a significant impact on the properties of a molecule that are of beneficial interest in both drug design and development. An early focus of the introduction of fluorine to aromatic rings was as a tactic to slow metabolism, although fluorinated rings are still subject to metabolic modification by CYP 450 enzymes and fluorine has been shown to undergo the NIH shift.(83) A particularly interesting and complex example of metabolism associated with a fluorophenyl ring is provided by the hepatitis C virus (HCV) NS5B polymerase inhibitor tegobuvir (132), which was discovered using a phenotypic cell-based screen.(84a) The fluorination pattern of this chemotype is a critical determinant of antiviral activity, illustrated by the SAR associated with 133–136 (Table 13), which were only understood as the result of a careful mechanistic analysis.(84b,c) Resistance mapping with 132 identified the NS5B polymerase as the antiviral target in the cell-based screen, but the compound was not a direct inhibitor of the enzyme in biochemical assays.(84b) Western blotting analysis of replicon cells treated with 132 revealed the presence of both the natural NS5B polymerase protein and a related protein with a molecular mass that was 820 Da higher. The modified NS5B protein represented the addition of one molecule of a metabolite of 132 that had lost one fluorine atom and acquired GSH. The antiviral activity associated with 132 was reversed by CYP 450 inhibitors, and this activity was subsequently narrowed to CYP 1A1 as the activating enzyme. The proposed metabolic pathway presented in Scheme 4 relies upon metabolism of 132 to the intermediate epoxide 137, which readily loses fluoride in a process presumably assisted by an electronic interaction with the imidazo[4,5-c]pyridine heterocycle, leading to the generation of the enone 139. This molecule offers two electrophilic sites that can react with GSH, with pathways A and B leading to the putative metabolites 140 and 141. However, GSH attack at the more hindered site outlined by pathway C would generate a molecule that retains electrophilicity and is capable of reacting with either GSH or a cysteine residue of the HCV NS5B protein. While the identity of the reactive cysteine in HCV NS5B was not definitively determined, Cys₃₆₆ was suggested as a potential candidate because it is proximal to the active site of the enzyme, and compounds that react with this residue are documented as inhibitors of the enzyme.(84b,d)

Table 13. HCV GT-1b Replicon Inhibitory Activity of NS5B Inhibitors 133–136

Aryl Fluorides: Membrane Permeability and P-gp Recognition

Substitution of a hydrogen atom by fluorine to introduce an intramolecular interaction with a pendent N–H has been exploited to enhance membrane permeability following the seminal observations made with the two series of inhibitors of the coagulation enzyme factor Xa (FXa) summarized in Table 14.(85) Caco-2 cell permeability was improved by substituting the hydrogen atom ortho- to the anilide N–H, illustrated by comparing the MMPs 145/146, 147/148, and 149/150. These observations were attributed to an electrostatic interaction between the F atom and the proximal N–H that shields the H-bond donor properties, important to both passive permeability and recognition by P-gp.(86,87) That the effect was not a function of the electron withdrawing properties of the substituent was illustrated by the poor membrane permeability associated with the linear nitrile moiety incorporated into 151. This structural motif is well-represented in the medicinal chemistry literature and is particularly prevalent in kinase inhibitors.(4a)

Table 14. Caco-2 Cell Permeability Values Associated with the Two Series of FXa Inhibitors 145–148 and 149–151

This phenomenon is not restricted to anilides but is also observed in benzamide derivatives and the presence of a proximal fluorine atom to interact with these H-bond donating functionalites are common in drug candidates, particularly kinase inhibitors. The effect of intramolecular interactions of this nature has been explored more explicitly by comparing the permeability properties in a parallel artificial membrane permeability assay (PAMPA) of 27 MMPs of N-phenylamides that differ by only a fluorine for hydrogen atom exchange (Figure 8A).(88) In 12 of the 27 cases examined, replacing the ortho- hydrogen by a fluorine atom led to an increase in permeability of ≥ +0.3 log P_e. The alternate arrangement represented by the benzamides depicted in Figure 8B was also examined by evaluation of 15 MMPs, of which 9/15 exhibited an increase in the permeability coefficient of ≥ +0.3 log P_e. A simple increase in lipophilicity was not the source of the enhanced membrane permeability because there was no demonstrable effect with meta-substituted fluorinated compounds. Moreover, the observation that introducing a fluorine atom had no effect in six out of the total of the 42 MMPs examined emphasized the contextual nature of this phenomenon. An analysis of the motifs depicted in Figure 8 in the Cambridge Structural Database (CSD) identified a number of examples where there were close contacts between fluorine atoms and the pendent N–Hs that stabilized the molecular conformation.(88)

Figure 8. Core structures of MMPs of N-phenylamides and benzamides examined in a PAMPA.

Another practical illustration of the value of engaging an NH by a proximal fluorine is provided by observations in the series of β-hydroxyethylamine-based inhibitors of the aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE-1).(89) The lead inhibitor 152 exhibited potent activity in a cell-based assay, but the brain/plasma ratio following oral administration to rats was low, attributed to P-gp-mediated efflux based on observations of compound performance in a human LLC-PK1 cell line, data that are summarized in Table 15. A potential solution to this problem was probed by introducing structural elements designed to interact with the acetamide N–H because of the known role of exposed N–Hs in P-gp recognition.(87) The methoxy moiety in 154, which is capable of establishing a conventional intramolecular H-bonding interaction with the N–H, exhibited 2-fold higher permeability and a 5-fold reduced efflux ratio while only modestly (2-fold reduction) affecting potency, data that contrasts with the properties of the iso-butyramide 153. The ortho-fluorobenzamide derivative 155 exhibited similar membrane permeability to 152 but P-gp recognition was reduced almost 20-fold based on the efflux ratio, while the data for 156 suggest that an alkyl fluoride can perform similarly. These observations are consistent with an interaction between the fluorine atoms and the N–H along with a reduction in the basicity of the C═O oxygen atom that masks these elements from the external environment and which is believed to compromise P-gp recognition.

Table 15. BACE-1 Inhibitory Activity, Membrane Permeability Data, and Efflux Ratios for 152–156

These effects were also manifested in the series of cyclic amidine-based BACE-1 inhibitors 157–160 in which the exocyclic NH₂ engaged the catalytic residues Asp₃₂ and Asp₂₂₈ of this aspartyl protease.(90) The lead compound 157 exhibited limited CNS penetration due, in part, to P-gp-mediated efflux, with a ratio of 12 determined from P_app values in Caco-2 cells. The introduction of a fluorine substituent in the peri position ortho- to the amidine carbon atom of 157 reduced the pK_a by 1.3 units from 8.4 to 7.1 in 158, a structural modification that increased membrane permeability while reducing the efflux ratio by almost 4-fold (Table 16). In this example, the positive effect on permeability was amplified in the matched pair of homologues 159 and 160, attributed to a weak interaction between the fluorine atom and one of the hydrogen atoms of the NH₂ that reduces the number of H-bond donors available to the environment. In addition, the solvation energy of the fluoro derivative was calculated to be less negative than for the hydrogen analogue, while the combination of electronic and steric effects was proposed to shield the polar nitrogen atom from the environment. In addition to the improvement in permeability and efflux ratio, BACE-1 inhibitory potency was retained for this series and an X-ray cocrystal structure of a close analogue of 160 revealed that the fluorine atom interacted with the carboxylic acid moiety of the catalytic Asp₂₂₈, the side chain hydroxyl of Thr₂₃₁, and three water molecules, with O to F distances that ranged from 2.9 to 3.3 Å.(90)

Table 16. BACE-1 Inhibition, Membrane Permeability, Efflux Ratio, and pK_a Values for 157–160

	R₁	R₂	BACE-1 IC₅₀ (nM)	P_app (10^–6 cm/s)	efflux ratio	pK_a of conjugate acid
157	H	H	500	3.4	12	8.4
158	F	H	158	12	3.1	7.1
159	H	CF₃	134	0.13	>10	ND
160	F	CF₃	241	39	0.6	6.9

Aryl Fluorides and Conformation of Proximal Substituents

A fluorine atom ortho- to the NH of an anilide also influences conformation, an effect exploited to illuminate the topology of the pharmacophore associated with the spiroindane-based calcitonin gene-related peptide (CGRP) receptor antagonist 161, which was evaluated as a potential therapeutic agent for the prevention of migraine attacks.(91) Although the oral bioavailability of 161 was reasonable, the PK profiles of more potent analogues were inferior, attributed to a high polar surface area (PSA) limiting absorption and focusing attention on replacing the central amide moiety with a less polar bioisostere. Modeling studies indicated a preference for coplanarity between the amide and spiroindane cores, with the lowest calculated energies observed at the two topologically divergent conformations of 0° and 180°. The preferred binding topology was probed by separately replacing each of the H atoms ortho- to the anilide by a fluorine to afford 162 and 163. It was anticipated that these substitutions would stabilize the complementary topologies depicted by the combination of an attractive electrostatic interaction between the N–H and fluorine and repulsive effects between the C═O oxygen and fluorine atoms due to steric and electrostatic considerations. Biological evaluation of isomers 162 and 163 demonstrated a 10-fold difference in CGRP receptor affinity favoring the extended conformation represented by 162, a hypothesis corroborated by the synthesis of the fused ring compound 164 that constrains the topology in an unambiguous fashion and preserves binding affinity.(91)

GPR119 agonists have been explored for their potential as a treatment for diabetes because they increase cAMP in in β-cells and stimulate insulin release, mimicking the effects of GLP-1. The introduction of a fluorine atom ortho- to the NH of the GPR119 agonist 165 afforded 166 with 8-fold improved potency, an effect that was not reproduced by the meta-fluoro analogue 167, which displayed potency similar to the progenitor (Table 17).(92) A similar SAR observation was made with the pair of related compounds 168 and 169, leading to the proposal that an intramolecular interaction between the fluorine and the N–H favored a planar conformation. This hypothesis was supported by the much weaker agonist activity associated with the N-methyl derivative 171 compared to the hydrogen analogue 170 and inspired the synthesis of bicyclic homologues as functional bioisosteres designed to constrain the preferred topology. The scaffold utilized in this exercise was of particular importance because the indoline 172 was found to be 10-fold more potent than the homologous tetrahydroquinoline 173.(92)

Table 17. hGPR119 Agonistic Activities Associated with 165–169

Aryl Fluorination and Solubility

An interesting observation of the effect of replacing a hydrogen atom ortho- to an anilide N–H by fluorine is provided by the CGRP receptor antagonist 175, derived from the progenitor 174.(93) The measured aqueous solubility of 175 was determined to be over 30-fold higher than that of 174, an observation not well understood, with conjecture focused on the fluorine atom polarizing the adjacent N–H, thereby rendering it a more powerful H-bond donor to promote enhanced solvation. However, this phenomenon may contribute to the poor membrane permeability and oral bioavailability associated with 175, which led to a focus on intranasal drug delivery for the treatment of migraine.(93)

Fluorine Mimicry with Nitrogen-Based Lone Pairs of Electrons

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Aromatic Fluoride and Azine Mimesis

The similarity of the dipoles of fluorobenzene and azine heterocycles has been recognized as a potential drug design element, and this bioisostere concept has been explored in several settings, with the results exhibiting a dependence on context.(4g,94−99) The dipole relationships between fluorobenzene and pyridine, 1,2-difluorobenzene and pyridazine, and 1,3-difluorobenzene and pyrimidine are depicted in Figure 9. Using a simpler metaphor of structural analogy, the electron density associated with the fluorine atoms may be equated with the lone pairs of electrons associated with the heteroatoms of the heterocycles. There are, however, some limitations to the isosteric relationship because the experimental dipole moments determined for fluorobenzenes are less than those measured for the analogous azine heterocycle.(99) Notably, the addition of the third fluorine atom in 1,2,3-trifluorobenzene increases the predicted dipole moment compared to either the 1,2- or 1,3-difluoro isomer, enhancing this aspect of mimicry with pyridine and pyrimidine.(100)

Figure 9. Comparison of the dipole moments and vectors of difluorinated benzenes and azines.

Bioisosterism between an aryl C–F and an azine C–N bond was examined as a means of addressing developability issues in a series of α2/α3 subtype-selective GABA_A agonists, explored as a potential treatment for anxiety.(95) Comparison of the receptor binding data accumulated for the MMPs 176/177 and 178/179 demonstrated effective bioisosterism between a C–F bond and a heterocyclic nitrogen atom in this context (Table 18). Of particular interest, 178 exhibited a poor PK profile due to the formation of the N-oxide at the exposed pyridine nitrogen atom in vivo. By replacing the ring nitrogen atom with a C–F moiety in combination with switching the other C–F to a nitrogen atom, both Log P and potency were maintained, while the PK profile was improved because the steric encumbrances surrounding the nitrogen atom in 179 interfered with N-oxidation. This type of structural isosterism may also be of value as a means of avoiding the CYP inhibition that is often associated with sterically exposed pyridine nitrogen atoms or mitigating susceptibility to aldehyde oxidase-mediated metabolism.

Table 18. SARs Associated with a Series of GABA_A α2/α3 Subtype-Selective Agonists 176–179

In the related GABA_A agonist 180, where the imidazo[1,2-a]pyrimidine heterocycle functions as an interesting and effective bioisostere of the pyridazine ring of 176–179, replacement of the nitrogen atom in the six-membered ring with a C–F moiety led to improved potency.(95b) This was illustrated by comparing the profiles of 182 with the pyridine prototype 180 and the C–H analogue 181, with 182 offering equivalent potency at both the α1 and α3 subtype receptors similar to 180 but with slightly higher efficacy at the α3 receptor and lower efficacy at the α1 subtype (Table 19). In this particular example, this was the targeted biochemical profile. In contemplating the design of 182, this study conducted what has probably been the most detailed analysis of C–F/azine bioisosterism. After careful consideration of the calculated and measured physicochemical properties of the abbreviated core heterocycles 183–185 compiled in Table 20, the C–F derivative 185 was determined to more closely resemble the aza analogue 183 based on dipole and electrostatic potential mapping. Moreover, 183 and 185 express similar pK_a values that are 2 units lower than for the C–H homologue 184, adding further to their functional resemblance; however, the Log D_7.4 value for 185 is closer to that of 184 than the more polar 183.(95b)

Table 19. SARs and Receptor Selectivity Associated with the Series of GABA_A Agonists 180–182

	X	α1 K_i (nM)	α3 K_i (nM)	α1 efficacy (% chlordiazepoxide)	α3 efficacy (% chlordiazepoxide)	μ of core (D)
180	N	0.71	0.47	60	79	5.10
181	C–H	4.35	5.16	35	61	3.37
182	C–F	0.20	0.32	34	104	4.52

Table 20. Calculated and Measured Properties for 183–185a

	X	calculated dipole (D)	measured pK_a	measured Log D_7.4
183	N	3.37 (R = CH₃)	4.9 (R = H)	–0.2 (R = H)
184	C–H	5.10 (R = CH₃)	6.9 (R = H)	0.8 (R = H)
185	C–F	4.52 (R = CH₃)	4.9 (R = H)	0.9 (R = H)

^{^a}

Structures were built and energy minimized using the Merck Molecular Mechanics Force Field (MMFF). The dipole values were extracted from an AM1 semiempirical calculation.

In the MEK inhibitor 186, the fluorine atom ortho- to bromine was observed to engage the backbone N–H of Ser₂₁₂, a stabilizing drug–target interaction that was an important contributor to potency.(96) More conventional H-bond acceptors were explored in the context of the fused heterobicyclic derivatives 187 and 188 where the exposed pyridine and imidazole nitrogen atoms, respectively, interact with the N–H of Ser₂₁₂. This illustrates a bioisosteric relationship between the C–F substituent of 186 and the heterocyclic nitrogen atoms of 187 and 188.(96)

Another example of an aryl C–F mimicking a pyridine atom was observed in a series of CHK1 kinase inhibitors.(97) The lead inhibitor 189, which was discovered using an affinity selection mass spectrometry-based automated ligand identification system screen, exhibited modest selectivity over CDK2 that was iteratively optimized into the more potent and selective pyridine-based inhibitor 190.(97) An X-ray cocrystal structure of 190 with the kinase revealed the important inter- and intramolecular interactions that contributed to the observed inhibitory potency (Figure 10).(97b) The key intermolecular interactions were catalogued as H-bonding between the pyridine ring nitrogen atom and the ammonium moiety of Lys₃₈ and a H-bond between the amide C═O of the isoindolinone and the N–H of Cys₈₇. In addition, there was a close association between the sulfur atom of the thiazole and the backbone C═O oxygen of Glu₈₅, which approach each other at a distance of 3.0 Å, less than the 3.32 Å sum of the van der Waals radii for the two atoms and one of the limited number of reported examples of an intermolecular oxygen lone pair to sulfur σ* interaction.(31) In addition, the planar topography associated with 190 was stabilized by an intramolecular O to S interaction between the isoindolinone amide oxygen and the thiazole sulfur atom which are closer than the van der Waals radii, separated by just 2.87 Å. The potency and selectivity of 190 was matched by the fluorobenzene analogue 191, in which the fluorine atom was suggested to be involved in either a charge–dipole or H-bonding interaction with the side chain ammonium of Lys₃₈.

Figure 10. Key interactions between CHK1 kinase and **190** in the cocrystal structure.

The effective pairing of the difluoro-benzimidazole 192 with cytidine in the context of RNA duplexes inspired an examination of the purine 193 and pyrrolo-pyrimidine 194 as functional mimetics.(98) These structural elements were incorporated as X into the 12-mer RNA 5′-CUU-UUC-XUU-CUU-3′, hybridized with the complementary strands 3′-GAA-AAG-YAA-GAA-5′ that incorporated each of the natural bases at Y and the melting temperatures of the duplexes determined. The results of this study are summarized in Table 21, with ParaFrag similarity scoring indicating that fluorobenzene was 45% similar to pyridine while chlorobenzene was of lower similarity at 27%. Interestingly, the ParaFrag scoring system indicated that in this context, a pyridine N-oxide was 25% similar while pyridone was just 22% similar to pyridine. Although these base pairings were less stable than the natural base pairs, 192 offers a relatively small energy difference compared to the natural bases, suggesting utility as universal base.(98)

Table 21. Melting Temperatures of 5′-CUU-UUC-XUU-CUU-3′ Hybridized with Complementary Strands 3′-GAA-AAG-YAA-GAA-5′

Fluorobenzene-azine bioisosterism has also been assessed in a series of mechanism-based inhibitors 195–204 of cathepsin L although the results were less than definitive.(99) In 195–204, the (hetero)aryl ring occupies the S₃ pocket of cathepsin L and π-stacking and dipole–dipole interactions were observed between these compounds and the backbone amide bond of Gly₆₇–Gly₆₈ of the enzyme (Figure 11). However, while the fluorinated phenyl derivatives 195–199 were effective mimics of their matched azine heterocycles 200–204, there was no clear correlation between the dipole moment of the (hetero)aryl ring and inhibitory potency. This was attributed to the proximity of the adjacent Gly₆₈–Leu₆₉ amide bond which adopts a complementary topology to that of Gly₆₇–Gly₆₈ such that the dipole is aligned in the opposite direction, believed to be a source of interference with the targeted effect.(99)

Figure 11. Structures and cathepsin L inhibitory data for **195**–**204**.

Nitrogen Lone Pair Mimesis by an Alkyl Fluoride

An interesting suggestion of isosterism between the piperazine nitrogen atom of the 5HT1_D and 5HT1_B receptor ligand 205 and the C–F bond of the 4-fluoropiperidine analogue 207 has been invoked to explain the SAR observations.(101) Piperazine 205 is rapidly absorbed in rats, but the piperidine analogue 206 exhibited a poor PK profile attributed to the highly basic nature of the nitrogen atom of this compound. The 4-fluoropiperidine 207 is less basic and displayed a similar in vitro receptor binding profile to 205 and 206 but was associated with much improved absorption in the rat. These observations led to the suggestion that the C–F bond of 207 may be mimicking the unprotonated nitrogen atom of 205 based on electronic considerations and dipole moments, depicted in simplistic terms in Figure 12, although other factors may underlie the observed SAR effects.

Figure 12. Proposed relationship between a piperazine lone pair of electrons and the fluorine atom of a 4-fluoropiperidine ring.

Flourination and Potency

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The judicious replacement of a hydrogen atom by fluorine can exert a significant effect on both the potency and specificity of a molecule, and examples where this change either enhances or erodes the potency of a molecule have been described that, perhaps not surprisingly, are dependent upon context. In several examples, the potency-enhancing effects associated with the introduction of fluorine have been traced to intermolecular interactions between the fluorine and the carbon atom of C═O moieties that are characterized as multipolar in nature or to interactions of fluorine with proximal H-bond donors that may have an electrostatic basis.(102) However, other intermolecular interactions and effects involving fluorine atoms of ligands have also been described and are summarized in the next section.

Multipolar and Hydrogen Interactions of Fluorine with Proteins

A detailed mechanistic understanding of how the fluorination of alkyl groups can lead to enhanced potency is provided by 208–215, a series of inhibitors of the binding of mixed lineage leukemia (MLL) to the tumor suppressor protein menin.(103) The fluorination patterns of the two alkyl moieties in 208–215 were found to play important roles in modulating potency based on the systematic SAR studies that are compiled in Table 22. In the X-ray cocrystal structure of 211 bound to menin, each of the CF₃ moieties were found to engage a backbone C═O of the protein in an orthogonal multipolar interaction. One F atom of the CF₃CH₂ substituent of 211 is 3.0 Å away from the backbone C═O of His₁₈₁, while a fluorine atom of the CF₃ that is bound to the thiadiazole is 3.4 Å away from the C═O of Met₃₂₂. The effect of modulating the thiadiazole substituent was explored in the context of the homologous series 208–211, where fluorination improved potency over the unsubstituted compound 208, with the exception of the monofluoromethyl derivative 209. The CHF₂ analogue 210 was found to be equipotent with the CF₃ derivative 211, and both were 9-fold more potent than the CH₃ prototype 208. X-ray cocrystal structures revealed that 208, 210, and 211 bound to the protein in a similar fashion and that one of the F atoms of 210 was 3.2 Å from the C═O of Met₃₂₂, while for 211, the fluorine to C═O carbon distance was 3.4 Å. However, for 209, the fluorine atom was oriented 38.5° out of the plane of the thiadiazole ring, located 3.7 Å away from the C═O carbon of Met₃₂₂, a distance that was considered to be too remote for a productive multipolar interaction. The conformation of 209 was unanticipated, and a quantum mechanics (QM) analysis suggested that the second fluorine atom of 210 stabilized a conformation that allowed one of the fluorine atoms to engage the C═O of Met₃₂₂. A similar SAR analysis conducted at the benzothienyl alkyl moiety in the context of the thiazolines 212–215 revealed that the CH₂F analogue 213 was almost 5-fold more potent than the CH₃ prototype 212, while the CF₂H analogue 214 offered an additional 4-fold potency improvement and this compound was just 1.5-fold weaker than the CF₃ derivative 215, the optimal compound in this subseries.

Table 22. SARs Associated with Inhibitors 208–215 of the Association of the Tumor Suppressor Protein Menin with MLL

These results of this study are consistent with an earlier seminal analysis of cocrystal structures in the Protein Data Bank (PDB), which revealed that fluorine atoms of ligands approached the backbone or side chain C═O moieties of a host protein closely (3.5 Å) and with an appropriate geometry in 16% (442 of the 2559) of the examples evaluated.(102) However, a few examples were highlighted where the effects of fluorine substitution were predicted to be beneficial but the experimental results were not supportive, emphasizing a need to be holistic when assessing the potential for orthogonal multipolar interactions between the fluorine atoms of a ligand and a protein.(102a) This is emphasized by an analysis of 247 matched pairs of compounds differing only by a fluorine for hydrogen exchange and for which there were both X-ray cocrystal structure data for the fluorinated compounds, and the fluorine atom was believed to be engaging in a multipolar interaction with the protein.(102b) In 67% of the examples in this data set, the fluorine was attached to a phenyl ring while the majority of the remaining compounds were CF₃ derivatives. The results of the analysis revealed a modest advantage in potency for the fluorinated compounds compared to the hydrogen analogues. After ignoring 79 compounds that were within 2-fold of the 1:1 correlation line as being within experimental error, 123 (73%) of the remainder experienced an increase in potency associated with fluorine substitution while the other 27% exhibited a reduction in potency of more than 2-fold. The average improvement in the pIC₅₀ value of the fluorinated compounds amounted to 0.36 log units, which translates to a free energy of binding advantage of approximately 0.5 kcal/mol. This reflects a modest but beneficial effect of fluorine substitution on potency that did not appear to be a function of increased lipophilicity; however, because the changes in both parameters were similar in magnitude, the effect on lipophilic ligand efficiency (pIC₅₀ – Log P) was neutral.(102b)

A fluorine for hydrogen substitution in the benzamidine-based thrombin inhibitor 216 led to a 5-fold enhancement of potency for 218, which was found to be 3-fold more potent than the 4-Cl analogue 217 and 5–10-fold better than the other fluorination patterns probed by 219–222.(104) An X-ray cocrystal structure provided an explanation for the observed SAR, which noted that the 4-fluoro atom was proximal to both the backbone C═O carbon atom (3.5 Å) and backbone C–H of Asn₉₈ (F to N distance = 3.1 Å), as summarized in Figure 13, productive interactions that are not available to either 216 or 217.

Figure 13. Key interactions between inhibitor **218** and thrombin.

A more recent example of the importance of fluorination on potency is provided by a series of carbazoles that stabilize the Tyr₂₂₀Cys mutant of the tumor suppressor protein p53.(105) In this inhibitor series, the CF₃ homologue 224 exhibited 5-fold improved binding affinity compared to the hydrogen-substituted prototype 223, an observation rationalized by an examination of the X-ray cocrystal structure. As illustrated in Figure 14, each of the three fluorine atoms of 224 was found to engage the protein, with two establishing multipolar interactions with the backbone C═O moieties of Leu₁₄₅ and Trp₁₄₆ while the third fluorine atom was proximal to the thiol of Cys₂₂₀, an association attributed to the combination of weak H-bonding and sulfur σ* interactions.(105)

Figure 14. Key drug–target interactions between the CF₃ substituent of **224** and the p53 protein.

In a series of potent inhibitors of Bruton’s tyrosine kinase (BTK), a fluorine scan identified a site for substitution that led to a 10–40-fold enhancement of potency.(106) The effect of fluorination was most effectively exemplified by the comparison of the matched pair of BTK inhibitors 225 and 226 (RN-486), where the introduction of a single fluorine atom increased potency by an order of magnitude.(106a,b) An X-ray cocrystal structure of the ethyl homologue 227, where the fluorine atom contributed to a remarkable 400-fold increase in potency in a human whole blood (HWB) assay over the hydrogen-substituted prototype 228, provided some understanding of the SAR observation. The fluorine atom of 227 was observed to be close to the protonated amine of Lys₄₃₀ (3.2 Å), the ortho C–H of Phe₄₁₃ (3.4 Å), and a conserved H₂O molecule (3.4 Å), as captured in Figure 15.(106a) Of note with respect to developability issues, while the cyclopropyl substituent in these analogues replaced a metabolically labile tert-butyl element, subsequent studies revealed a metabolic liability associated with the pyridone ring which was susceptible to CYP 450-mediated bioactivation and trapping by GSH, attributed to an initial epoxidation of the C-5,C-6-double bond. This problem was relieved by further optimization in which the pyridone ring was replaced by a pyridazin-3-one heterocycle but not when a pyrazine-2-one was used as the scaffold.(106c)

Figure 15. Key drug–target interactions between inhibitor **227** and BTK.

The CF₃ substituent in 230, an inhibitor of the Q₀ site of the cytochrome bc₁ complex, enhanced potency by an order of magnitude when compared to the CH₃ prototype 229.(107) An X-ray cocrystal structure of 230 with the chicken enzyme revealed close contacts (2.45–2.98 Å) between the fluorine atoms and two hydrogen atoms of Pro₂₇₀, three hydrogen atoms of Ile₁₄₆, and two hydrogen atoms in each of Tyr₂₇₈ and Phe₂₇₄ of the protein.(107)

The CF₃ Moiety and Tetrel Bonding

A weak but nevertheless interesting interaction between the CF₃ moiety and electron rich centers of proteins (CO₂^–, amide carbonyl, and the oxygen atoms of serine, threonine, and tyrosine) that involves tetrel (CF₃···O) bonding has recently been catalogued.(108) Molecular electrostatic potential (MEP) mapping of perfluorotoluene revealed a π-hole associated with the aromatic ring calculated to be +32.9 kcal/mol and a small region of positive potential at the sp³ carbon atom that characterizes a σ-hole that was calculated to be +16.9 kcal/mol (Figure 16).(108) The larger MEP value of the π-hole suggested that the dominant interactions of electron rich species with perfluorotoluene would be at this site, substantiated by calculations of the interaction energies of the π- and σ-holes with NH₃, the carbonyl oxygen atom of acetone, formic acid anion, and phenoxide. The geometry of the interaction of electron rich species with the σ-hole associated with the CF₃ substituent is highly directional in nature, optimal at an angle of 180° to the Ar-sp³ carbon bond.

Figure 16. Calculated energies of the σ-hole and π-hole associated with perfluorotoluene.

To develop insight into the contribution of this interaction in protein–ligand structures, a search of the PDB was conducted using parametric restraints that required a resolution factor of ≤3.0 Å, a distance between the carbon atom of the CF₃ substituent of a ligand and the oxygen atom of the protein of less than 3.37 Å (the sum of the van der Waals radii of the two atoms: 1.7 Å for C and 1.52 Å for O) and an X–C···O angle of >160°. This process identified eight complexes where the carbon to oxygen distances ranged from 2.59 Å in the case of 231 interacting with the side oxygen atom of Asn₉₇ of macrophage migration inhibitory factor to 3.35 Å for the Asp_312B side chain carboxylic acid of the Arg₁₄₀Gln mutant of mitochondrial isocitrate dehydrogenase 2 (IDH2) interacting with AGI-6780 (232).(109,110a) Two examples were examined in detail as illustrative of the phenomenon: the IDH2 inhibitor AG-221 (234) in complex with the enzyme and niflumic acid (235) in complex with the NmrA-like family domain containing protein 1 NMRAL1.(109,110b,111) The key aspects of drug–target interactions between 234 and 235 and their protein partners are captured in Figures 17 and 18, respectively. In the case of 234, the side chain carboxylate of Asp₃₁₂ interacted with the CF₃ of the inhibitor, while for 235, the hydroxyl O atom of Tyr₂₄₆ was the partnering element. It was suggested that a potential indicator of the contribution of tetrel bonding to the interaction of 234 with IDH2 is provided by the profile of the des-CF₃ derivative 233 which is 2-fold weaker; however, because this is data from a cell-based assay, it represents at best an imprecise index.

Figure 17. Key interactions between **234** and IDH2 in the cocrystal stucture.(110b)

Figure 18. Key interactions between **235** and the NmrA-like family domain containing protein 1 NMRAL1 in the cocrystal complex.(111)

Indomethacin (236) is a potent but nonselective inhibitor of the COX-1 and COX-2 enzymes, a profile that can be modified by fluorination of the 2-methyl substituent, illustrated by 237, which is a selective but 2-fold weaker inhibitor of COX-2 (Table 23).(112) Detailed kinetic studies revealed a K_i for human COX-2 of 13 μM for 236 and 1.5 μM for 237, while studies with a series of site-directed mutant enzymes indicated that the two compounds very likely bound to the enzyme in a similar fashion. Modeling studies suggested that the CF₃ moiety of 237 filled a small hydrophobic pocket in the enzyme in a differential fashion, as detected by differences in inhibitory potency toward mutant COX-2 enzymes. In particular, the inhibitory activity of 237 toward the Val₅₂₃Ile COX-2 mutant enzyme was reduced by more than 15-fold compared to a smaller 3.7-fold reduction for 236. However, because in the cocrystal structure Val₅₂₃ is located proximal to the 5-OCH₃ moiety of 236, the data were interpreted as being the result of the larger CF₃ substituent causing displacement of the heterocyclic core toward the center of the binding pocket. This arrangement was postulated to induce a more significant steric clash between the 5-OCH₃ substituent and the larger isoleucine side chain of the mutant enzyme.(112)

Table 23. Cyclooxygenase Inhibitory Profile of 236 and Its Fluorinated Homologue 237

	236	237
R	CH₃	CF₃
ovine COX-1 IC₅₀	27 nM	>100 μM
mouse COX-2 IC₅₀	127 nM	267 nM

Another example of the introduction of a CF₃ moiety contributing to increased potency is provided by the series of HCV NS3 protease inhibitors 238–240, where both the intrinsic enzyme inhibitory potency and the antiviral activity in cell culture exhibited a dependence on the absolute configuration of the trifluoromethylated carbamate moiety that projects into the S₄ subpocket of the enzyme, data that are summarized in Table 24.(113) In the absence of cocrystal structure data, rationalization of the observation focused on modeling studies that placed the CF₃ moieties of the two diastereomers in different interactive relationships with the enzyme, with that of 240 suggested to exhibit a closer contact with the protein.

Table 24. SARs Associated with HCV NS3 Protease Inhibitors 238–240a

^{^a}

^†Biochemical enzyme inhibition assay. ^‡Cell-based HCV replicon assay.

Fluorination patterning has been shown to play an important role in modulating both the potency and species selectivity of triazolopyrimidine-based inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (Pf DHODH) that have been probed as therapeutic agents for the treatment of malaria.(114) While the prototype triazolopyrimidine 241 was inactive in both biochemical and cell-based assays, the introduction of a para-CH₃ substituent to the phenyl ring afforded the homologue 242 as a compound exhibiting modest inhibitory activity in both assays (Table 25). However, the CF₃ analogue 243 was 15-fold more potent than 242, while the introduction of a CH₃CH₂ at C-12 (244) improved potency by a further 3–5-fold. In these compounds, the aniline N–H engages His₁₈₅ in the active site of the enzyme in a H-bonding interaction that is a source of selectivity toward the malaria enzyme over the human homologue. The binding modes of these compounds differ between the two enzymes, with the N–H engaging His₅₆, the residue in the human enzyme equivalent to His₁₈₅, via the intermediacy of a H₂O molecule. Additional optimization focused in fluorination of the C-12 substituent to give 245 which inhibited Pf DHODH with an IC₅₀ value of 38 nM and was active in the cell-based assay with an EC₅₀ value of 10 nM. The in vitro antimalarial profile of the SF₅-containing DSM-265 (246) was similar to that of the CF₃ analogue DSM-267 (245), and these two compounds offered an optimal compromise between potency and metabolic stability for the series of 4-substituents that were examined. However, in an animal model of infection, 246 offered a potency advantage while a more linear dose-exposure profile was observed in rats, leading to its selection as a candidate for clinical evaluation. The IC₅₀ values for Pf DHODH inhibition were 33 nM for 246 and 38 nM for 245 and both compounds weak inhibitors of the human enzyme, IC₅₀ values >100 μM; however, rodent enzymes were found to be more susceptible, with the IC₅₀ values for mouse and rat measured as 2.3 and 2.7 μM, respectively, for 246, and 24 and 7.2 μM for mouse and rat, respectively, for 245. Interestingly, the species specificity of inhibition was found to be highly sensitive to the fluorination pattern of the aniline ring with the additional fluorine atoms ortho- to the CF₃ substituent of analogues of 243–245 enhancing inhibition of the mammalian enzymes by 5–100-fold. This phenomenon was attributed to an increase in the entropic contribution to binding as a consequence of favorable hydrophobic interactions established between the fluorinated inhibitors and leucine residues in the mammalian enzymes, suggested as evidence that fluorination of a molecule can enhance binding to the lipophilic pockets of proteins.(114)

Table 25. SARs Associated with Triazolopyrimidine-Based Pf DHODH Inhibitors 241–246

	R	X	R₁	Pf DHODH IC₅₀ (μM)	Pf 3D7 cells EC₅₀ (μM)
241 (DSM12)	H	CH	H	>200	>100
242 (DSM97)	H	CH	CH₃	4.2	6.4
243 (DSM74)	H	CH	CF₃	0.28	0.34
244 (DSM280)	CH₃CH₂	CH	CF₃	0.087	0.058
245 (DSM267)	CH₃CF₂	CH	CF₃	0.038	0.010
246 (DSM265)	CH₃CF₂	CH	SF₅	0.033	0.046

An unusual effect that was observed when aryl hydrogen atoms were replaced with fluorine is found by comparing the activity profiles of the Aurora A kinase inhibitors 247–249.(115) The mono-fluoro compound 248 was 2-fold more potent than prototype 247 in both a functional and binding assay, while potency was further enhanced by introducing a fluorine atom to the pyrimidine ring to give 249. However, the most interesting observation arose from an analysis of X-ray cocrystal structures which revealed substantially different biochemical modes of inhibition for 247 compared to 248 and 249. In the X-ray cocrystal structure of Aurora A kinase with 247, the DFG loop was in the active DFG-in conformation, stabilized by an interaction between Asp₂₇₄ and Lys₁₆₂. Attempts to soak 248 into crystals of Aurora A kinase were unsuccessful, suggesting that binding required changes to the crystal lattice. After developing conditions for cocrystal formation, the X-ray structures of both 248 and 249 revealed that the DFG loop had flipped to the DFG-out conformation based on rotation about the Ala₂₇₃ amide carbonyl (Figure 19). In this conformation, Asp₂₇₄ was rotated ∼100° away from the ATP binding site and there was substantial rearrangement of intramolecular interactions within the protein. This effect on enzyme conformation was also observed with the chloro-, bromo-, and cyano- homologues of 248 but not with the CF₃-, CF₃O-, or phenyl-substituted analogues, arguing against a steric effect as the source. In the cocrystal structure, the fluorine atom was 3.8 Å away from the carbon atom of the CH₃ side chain substituent of Ala₂₇₃, with the C–F bond aligned almost collinearly with the vector of the C_α–C_β bond. For Cl and Br, the measured distances were shorter at 3.4 Å, but the geometry remained collinear. These observations were interpreted in the context of an induction of a dipole in the C_α–C_β bond of Ala₂₇₃ by the C–F dipole of the ligand that was transmitted to the amide C═O, thereby facilitating rotation of the peptide backbone, as summarized in Figure 19.

Figure 19. Proposed dipole interactions between **248** and Aurora A kinase leading to a conformational change in the DFG loop of the enzyme.

Fluorine and the Modulation of the Basicity of Amines

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The high electronegativity associated with a C–F bond has made introduction of fluorine a useful approach to modulate the basicity of proximal amines without introducing additional polarity, with effects that are quantitatively predictable based on the number of fluorine atoms and their connectivity with the nitrogen atom.(116) A careful analysis of the fluorination pattern of a series of tetrahydroisoquinoline-based inhibitors of phenylethanolamine N-methyltransferase (PNMT), the enzyme that methylates norepinephrine to produce epinephrine, led to the identification of compounds with improved selectivity because binding to the α₂ adrenoreceptor subtype was a problem inherent to this chemotype.(117) As summarized in Table 26, the successive introduction of fluorine atoms to the CH₃ moiety of 250 led to stepwise reductions in the basicity of the tetrahydroisoquinoline heterocycle in homologues 251–253. Fortunately, PNMT inhibitory potency proved to be less sensitive to a reduction in basicity than did binding to the α₂ adrenoreceptor, allowing the sought-after balance of selectivity to be achieved with the CHF₂ derivative 252.

Table 26. Basicity, PNMT Inhibition, and α₂ Adrenoreceptor Affinity for the Tetrahydroisoquinolines 250–253

	R	pK_a of conjugate acid	K_i PNMT (μM)	K_i α₂ (μM)	PNMT selectivity
250	CH₃	9.29	0.017	1.1	65
251	CH₂F	7.77	0.023	6.4	280
252	CHF₂	6.12	0.094	230	2400
253	CF₃	4.33	3.2	>1000	>310

An interesting application of the effect of modulating amine basicity by replacing a hydrogen atom with a fluorine is found in 255, a mono-fluoro analogue of the potent μ opioid agonist fentanyl (254).(118) The design of 255 explored the hypothesis that peripheral μ opioid receptors are upregulated in painful syndromes and contribute to the sensation of pain. In addition, tissues at sites of damage that produce pain are associated with inflammation and a lower pH, providing a unique environment that could be taken advantage of to modulate the selectivity of action of 254 in a fashion that would spare receptor activation in normal tissues. The hypothesis was based on the understanding that the protonated form of the highly basic 254, pK_a > 8, that predominates at physiological pH is that recognized by the receptor where it engages Asp₁₄₇. The introduction of a single fluorine atom to the piperidine ring of 254 to afford 255, evaluated as a mixture of diastereomers, reduced the measured pK_a value to 6.8 and, as such, this compound would be substantially protonated only at pH values that are below those characteristic of normal physiological conditions. Binding experiments conducted in human embryonic kidney cells transfected with the μ opioid receptor indicated that the affinity of 254 was independent of pH with the K_i value at pH = 7.4 = 1.1 nM while 255 bound less potently at physiological pH, K_i = 17.9 nM, than pH = 5.5, K_i = 7.3 nM, and pH = 6.5, K_i = 3.7 nM. This profile would favor binding of 255 to the μ opioid receptor only at lower pH values, providing a measure of selectivity based on local tissue conditions. Thus, 255 was anticipated to activate the μ opioid receptor at the source of pain generation where the pH is believed to be lower than 7.4. In a series of in vivo studies, 255 produced analgesia in rats in an injury-restricted fashion in two different models of inflammatory pain that, in contrast to 254, was reversed by a peripherally active, non-CNS penetrant μ opioid receptor antagonist. Consistent with the proposed selectivity profile, 255 was devoid of the respiratory depression, sedation, and constipation side effects associated with 254 and exhibited reduced addiction potential as measured by a conditioned place preference evaluation.(118)

In a series of inhibitors of kinesin spindle protein (KSP), a member of a family of motor proteins that was explored as a mechanism for the treatment of taxane-refractory solid tumors, it was determined that P-gp recognition was sensitive to the basicity of a core piperidine moiety.(119) A pK_a value of 6.5–8.0 was determined to be optimal for maximal efficacy in a tumor cell line by reducing efflux, and this was achieved by both the N-cyclopropyl and N-fluoroethyl derivatives 256 and 257, respectively. However, 256 displayed time-dependent CYP 450 inhibition in vitro, a known liability of cyclopropyl amines, while evaluation of 257 in vivo revealed toxicity consistent with the release of fluoroacetic acid as a consequence of N-dealkylative metabolism. The solution to this problem was to install a fluorine atom in the piperidine ring where the effect on pK_a was found to be sensitive to disposition, with the axial compound 258, which was selected for clinical evaluation, more basic than the equatorial isomer 259.(119a)

In the structurally related series represented by prototype 260, modulation of P-gp by fluorination of the primary amine-containing side chain identified both 261 and 262 as satisfactory solutions with efflux ratios of 3 and 5, respectively, compared to the much higher value of 1200 recorded for 260.(119b)

The introduction of a fluorine atom at the bridgehead position of the quinuclidine-based α7-N-acetylcholine receptor inhibitor 263 afforded 264, a compound with a 2.5 unit lower pK_a value that effectively addressed the Caco-2 efflux problem associated with the more basic parent compound.(120) Unfortunately, this structural modification also resulted in a significant erosion in receptor recognition.

Control of basicity is also an approach that has been exploited to modulate the binding of inhibitors to the hERG cardiac potassium channel, a phenomenon that has been associated with the occurrence of arrhythmias in humans, and the induction phospholipidosis, off-target liabilities that have been suggested to possess overlapping pharmacophores.(121) For example, reduction in the electron density and Log P value of the pyridine heterocycle of the JAK3 inhibitor 265 was examined as an approach to reducing the affinity of this compound for the hERG channel.(122) As captured in Table 27, the installation of a fluorine atom in the piperidine ring reduced hERG binding by an order of magnitude without a significant change in the calculated Log P value that was accompanied by a 4-fold increase in potency for the (3S,4R) isomer 267 compared to prototype 265. The (3R,4R) isomer 266 was several fold less potent than 267 but was also poorly recognized by the hERG channel.

Table 27. JAK3 Inhibitory Potency, hERG Binding, and Calculated Log P Values for 265–267

	R	R′	JAK3 IC₅₀ (nM)	hERG binding (μM)	cLogP
265	H	H	1.3	13.4	2.8
266	F	H	1.7	>100	2.7
267	H	F	0.3	>100	2.7

A fluorine for hydrogen exchange was also taken advantage of as an approach to modulate the basicity of the oxazine-based BACE-1 inhibitor 268 in order to improve membrane permeability and reduce P-gp-mediated efflux from the CNS compartment.(123) The amino oxazine ring system had been specifically selected as the scaffold to present the key amidine pharmacophore based on calculations conducted a priori that predicted moderate pK_a values. However, the experimental pK_a values revealed the predictions to be inaccurate, with measured values considerably higher than had been anticipated. This was exemplified by the prototype 268 for which the measured pK_a was 9.6, over 3 units higher than the predicted value of 6.4 based on the calculations. After subcutaneous administration to mice, the measured brain levels for 268 were low and the compound was found to be subject to P-gp-mediated efflux in vitro. The introduction of several fluorinated elements to the oxazine ring was contemplated as a means of further refining the basicity, with C-2 selected as the optimal site based on an analysis of the X-ray cocrystal structure where this vector was directed toward the flap residues, offering potential to productively engage the protein. In the event, a simple 2-fluoro substituent proved to be the most effective modification, reducing the pK_a value of the amino oxazine by 1.2–1.4 units. However, potency was shown to be dependent upon the absolute configuration of the newly introduced chiral center because the axial (2S)-isomer 270 was less potent and less basic (IC₅₀ = 102 nM, pK_a = 7.6) than the equatorial (2R)-isomer 269 (IC₅₀ = 12 nM, pK_a = 7.8). The reduced basicity enhanced the correlation between enzyme inhibitory potency and activity in the cell-based assay, which was attributed to reduced accumulation of compounds in the acidic endosomal compartment where BACE-1 is located. However, 269 exhibited low metabolic stability, and the more stable pyridine nitrile 271 was subsequently selected for evaluation in in vivo studies where a dose-related reduction in Aβ42 levels in CSF was observed, with a 90% decline measured following drug dosing at 2.5 mg/kg to dogs.(123)

N-CF₃ Derivatives

N-Trifluoromethyl amines represent an emerging functionality that compromises the basicity of an amine but have only been cursorily explored as an element in drug design, presumably a function of issues associated with synthetic access.(124) A recent article has described a facile synthesis of N-CF₃ derivatives using a mild preparative procedure that is compatible with late-stage functionalization. The developed process relies upon the reaction of an amine with (Me₄N)SCF₃ and AgF in CH₃CN or CH₂Cl₂ and the N-CF₃ derivatives of anilines, cyclic amines, and alkyl amines were prepared in good yield using this protocol. Included in the survey was the preparation of 272–274 which are the N-CF₃ analogues of the PDE-5 inhibitor sildenafil, the antifungal agent terbinafine, and the tricyclic antidepressant amitriptyline, respectively. Unfortunately, these compounds were not evaluated in the appropriate assays to determine if biological activity was preserved or in in vitro assays that would offer insight into drug developability properties and potential issues.(124)

The best documentation of an N-CF₃ derivative that has been assessed biologically in vitro is provided by the quinolone 276, which was tested in the series of antibacterial assays summarized in Table 28.(125) The inhibitory profile of 276 toward both Gram-positive and Gram-negative bacteria was comparable to the N-CH₃ homologue 275, with some possible advantage for 276 with respect to inhibition of P. aeruginosa.

Table 28. Antibacterial Activity Associated with the N-CH₃-Substituted Quinolone 275 and Its N-CF₃-Substituted Homologue 276

		Gram-positive		Gram-negative
	R	S. aureus Smith	St. pneumoniae type III	E. coli NIHJ JC-2	P. aeruginosa IID1210
275	CH₃	0.78	3.13	0.05	6.25
276	CF₃	0.39	6.25	0.05	1.56

The purine 277 was prepared as the sole N-CF₃ derivative in a series of Cdk2 inhibitors, and this compound inhibited the enzyme with an IC₅₀ value of 1 μM.(126) Unfortunately, the matching N-CH₃ analogue that would allow a direct comparison was not made but the Cdk2-inhibitory activity of 277 was comparable to similar alkyl-substituted analogues in the broader series.

Fluorine and Carbonyl Bioisosterism

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A number of drug design initiatives have sought to take advantage of fluorine-containing functionality as bioisosteres of the carbonyl functionality. However, while there has been some focus on mimicking the amide functionality, which will be discussed later, there are examples of the use of fluorinated elements as bioisosteres of the carbonyl moiety of ketones, lactones, and carboxylic acids. In this section, representative examples are discussed that demonstrate functional bioisosterism in a range of biochemical contexts, with the underlying design principles in some cases supported by X-ray cocrystallographic data.

sp³ C–F as a C═O Bioisostere

Mimicry of C═O by a C–F is a function of the similarity between bond lengths, van der Waals radii and dipoles of the two functionalities and the electronegativity of oxygen and fluorine. A successful application of C═O/C–F bioisosterism can be found in studies with camptothecin (278), a naturally occurring alkaloid derivative that potently inhibits topoisomerase I and prevents tumor cell proliferation in vitro with EC₅₀ values of <1 μM.(53b,127) However, in vivo applications of 278 are limited, in part, by the low chemical and metabolic stability associated with the lactone ring which is hydrolyzed rapidly to the inactive carboxylic acid derivative. Replacing the lactone C═O with an α-fluoro ether moiety was examined as a potential bioisostere based on an appreciation of the similarity of dipoles of the C–F and C═O bonds.(127) The (2R)-isomer 279 was a significantly less potent inhibitor of both topoisomerase I enzyme-mediated relaxation of supercoiled DNA and tumor cell proliferation in vitro than the (2S)-isomer 280. However, in assays measuring stability in H₂O at pH = 7.4, the fluoro ether ring of 280 was found to offer superior performance when compared to the lactone 278. Lactone 278 was degraded by >50% after 6 h of incubation compared to a loss of just 4% for 280, with a similar profile observed in phosphate buffer. The antiproliferative potency of 279 was fully restored to the levels offered by 278 by decoration of the quinolone core, with the C-7 cyclohexyl derivative 281 optimal. This compound demonstrated dose-related inhibition of tumor growth in two xenograft models following IP administration of doses of 2–4 mg/kg, with efficacy comparable to topotecan (282), a camptothecin derivative, at a dose of 0.5 mg/kg. Notably, administration of 281 at 2 mg/kg was not associated with the weight loss observed with 0.5 mg/kg doses of 282.

Fluoro Alkenes and Aromatic Fluorides as C═O Bioisosteres

Fluoro- and trifluoromethyl-alkenes and chloroalkenes have been proposed as potential amide bioisosteres based on the topological, steric, and electronic relationships illustrated in Figure 20, and some of these structural elements have found application in the design of both small molecule drugs and peptidomimetics.(8,128−132) However, while the geometries are similar, the dipoles associated with the fluorinated and chlorinated olefins are of a lower strength when compared to an amide, more comparable to an aldehyde or ketone, and although the dipole vectors are similarly aligned, DFT calculations indicate that a chloroalkene more closely approximates an amide than a fluoroalkene.(133,134)

Figure 20. Dipole moments and vectors that illustrate isosterism between an amide moiety and fluorinated alkene derivatives that contrasts with simpler alkenes.

Examples of Fluorinated Alkenes As Amide Bioisosteres

An example where a fluoroalkene functions as an effective amide replacement when embedded in a peptidomimetic background is provided by studies with Leu-enkephalin (283), a pentapeptide that activates the δ-opioid receptor but fails to produce analgesia in vivo due to poor PK properties.(131) The ester 284 and thioamide 285 retained δ-opioid receptor activity, indicating that a H-bond donor at this site was not essential and inspired the design of the fluoro olefin 286. The potent activity of 286 confirmed the H-bonding hypothesis, while the weaker receptor binding affinity associated with the simple olefin 287 emphasized the importance of the fluoride atom for effective functional mimicry.

A fluoro alkene was also examined as a replacement for the amide moiety at the Tyr¹–Gly² junction as an approach to interfering with metabolism at this site.(132) The Leu-enkephalin analogue 288 demonstrated significant activity toward activating the δ- and μ-opioid receptors stably expressed in CHO cells, although the EC₅₀ values were 60- and 45-fold higher, respectively, than for progenitor 283. However, differentiation was observed at the κ-opioid receptor where the activity of 288 was negligible compared to 283, which expressed an IC₅₀ value of 80 nM.(132)

Both a fluoro- and a chloro-alkene were found to be effective amide mimetics when installed in a 36-residue peptide derived from the amino terminus of human parathyroid hormone (hPTH), where they were incorporated as part of a dipeptide element installed at the amino terminus.(134) Comparison of the matched pairs 289/290 and 291/292 indicates that in this context, the fluoro- and chloro-alkenes performed similarly with respect to binding to the PTH receptor and expression of full intrinsic activity as measured by cAMP production, with the exception of 289, which acted as a partial agonist (Table 29).(134b)

Table 29. hPTH Receptor Binding Data for 289–292

A¹-A²-Ser³-Glu-Ile-Gln-Leu-Met-His-Asn¹⁰-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg²⁰-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp³⁰-Val-His-Asn-Phe-Val-Ala-NH₂
	X	R	binding affinity to opossum kidney (OK-1) cells (pK_D)	cyclic AMP OK1 EC₅₀ (nM) (intrinsic activity
289	F	CH₃	8.2	9.1 (0.6)
290	Cl	CH₃	8.9	5.5 (1.0)
291	F	iPr	8.9	4.4 (1.0)
292	Cl	iPr	8.9	7.9 (1.0)

A fluoro-olefin was examined as a potential amide bioisostere in DPP-4 inhibitors in an attempt to confer resistance to cleavage by amidases or proteases, with 294 found to be 5-fold less potent than its matched amide 293, attributed to the weaker dipole associated with the former.(135) However, potency was enhanced by variation of both the P₁ moiety and the pattern of substitution on the phenyl ring, with 295 a considerably more potent DPP-4 inhibitor. An X-ray cocrystal structure of 295 bound to the enzyme revealed a similar binding mode to an amide homologue, with the fluorine atom of the bioisostere proximal to the side chain N-Hs of Arg₁₂₅ and Asn₇₁₀, described as a H-bonding interaction.(135)

A conformational analysis of the symmetrical and potent HCV NS5A inhibitor daclatasvir (296) revealed that the most stable conformers were those stabilized by an intramolecular H-bond between the valine carbonyl oxygen atom and the imidazole N–H (distance = 2.2 Å).(136) This topography resembled that of a γ-turn and inspired the design of a fluoro-alkene amide bioisostere in which both of the valines of 297 were predicted to adopt a similar conformation, with the fluorine to imidazole N–H distance predicted to be 2.29 Å. In contrast, the analogue 298, in which the conformational constraint associated with the cylcopentane ring of 297 was relaxed, was predicted to exhibit a much lower propensity to adopt a γ-turn topography. In a GT-1b HCV replicon assay, although 297 was several fold weaker than 296, it still maintained subnanomolar inhibitory potency.(136a) However, in both GT-1a and GT-2a replicons, 297 was substantially (>2500-fold) less active than 296, demonstrating the heightened sensitivity of these two genotypes to structural changes in the molecule.(136b) The antiviral effects of 298 were of lower potency, lending some support to the fundamental design principle.

Fluorinated olefinic peptide nucleic acids 301 (F-OPAs), patterned after peptide nucleic acids 299 (PNAs), were prepared with adenine, thymidine, and guanine as the bases and incorporated into decameric oligomers for evaluation of the stability of the duplexes with complementary strands of DNA.(137) The stability, as determined by T_m values, was dependent upon the location of the nucleotide mimetic in the sequence, and while fully modified F-OPA decamers and pentadecamers formed parallel duplexes with complementary DNA, their stability was lower than either the peptide nucleic acid analogue 299 or OPA analogue 300.

Aromatic Fluorides as C═O Bioisosteres

An aromatic fluoride, which may be viewed as incorporating an embedded alkenyl fluoride, has been shown to effectively substitute for a lactam carbonyl moiety in several biochemical contexts. Prominent examples where a bioisosteric relationship is supported by X-ray cocrystal structure data have been provided by inhibitors of enzymes in the coagulation cascade, studies that have provided detailed insights into structural emulation.(138,139) Comparison of the MMPs 302 and 303, which are dual tissue factor VIIa (FVIIa) and thrombin (FIIa) inhibitors and prototype molecules in their respective series, provide an index of the level of functional mimicry, with the fluorophenyl moiety approximately an order of magnitude less potent in both enzyme assays.(138a,b) An X-ray cocrystal of the analogue 304 with FVIIa revealed that the fluorine atom was close to the N–H of Gly₂₁₆ (N to F distance = 3.4 Å) in a fashion that was reminiscent of the H-bond observed between the carbonyl oxygen atom of the amide-based inhibitors (Figure 21).(138) In this structure, the iso-propyl-substituted aniline N–H of 304 donated a H-bond to the backbone C═O of Gly₂₁₆, with the N to O distance measured as 3.4 Å.

Figure 21. Key interactions between and FVIIa and the benzamidine-based inhibitor **304**.

Comparison of the data for the matched pair of thrombin inhibitors 305 and 306 suggests the potential for a bioisosteric relationship between the fluorophenyl and pyridine N-oxide moieties although the H-bonding properties of the two elements are considerably different, with the N-oxide moiety the more powerful acceptor.(139b,c,140)

A fluorobenzene motif has also been found to be an effective amide bioisostere when incorporated into allosteric inhibitors of the HCV NS5B RNA-dependent RNA polymerase, with 307 the prototype of the series.(141) The 2-fluoro derivative 309 was a potent inhibitor of NS5B biochemical activity in vitro, a profile that extended to the 2,4-difluoro homologue 310. However, the des-fluoro analogue 308 and the 3,4-isomer 311 were found to be less potent, data that collectively emphasized the importance of the topology of fluorine patterning and were concordant with the idea that the C–F moieties in 309 and 310 mimic the C═O of 307. An X-ray cocrystal structure of 309 with the NS5B enzyme revealed that hydrophobic interactions were dominant, with no specific interaction observed between the carboxylate element and the protein (Figure 22). However, the fluorine atom of 309 was close to the backbone NH of Tyr₄₄₈ with a nitrogen to fluorine distance of 2.6 Å, while the hydrogen atom ortho- to the fluorine substituent was 2.9 Å from the backbone carbonyl oxygen atom of Ile₄₄₇, a distance less than the sum of their van der Waals radii that was suggestive of a C–H H-bonding interaction.(140c,141)

Figure 22. Key drug–target interactions between **309** and the HCV NS5B polymerase protein.

In a series of non-ATP competitive MAP kinase kinase 1 (MEK1) inhibitors, the fused pyridone 312 exhibited an IC₅₀ value of 38 nM.(142,143) Although clearly not a MMP, the difluorobenzene homologue RO4987655 (313) demonstrated high inhibitory potency toward the kinase, and this compound was advanced into phase I clinical trials.(144) An X-ray cocrystal structure of the bromobenzene derivative 314 bound to MEK1 was informative, revealing an intramolecular H-bond between the N–H and the C═O oxygen atom of the hydroxamic acid ester (Figure 23).(143,144) In addition, there was a halogen bonding interaction between the iodine atom and the backbone carbonyl oxygen atom of Val₁₂₇ while the 4-fluoro atom was close to the backbone N–H moieties of both Ser₂₁₂ and Val₂₁₁.

Figure 23. Key drug–target interactions between MEK1 and inhibitor **314**.

Several additional examples where there is evidence of a bioisosteric relationship between the C–F and C═O moieties have been described. In a series of pyridone-based fused tricyclic human androgen receptor (hAR) antagonists of which 315 is representative, examination of the potential of a bioisosteric relationship between the C–F and C═O moieties was adopted as an approach to understand which pyridone tautomer was responsible for the drug–target interactions.(145) The assays for assessing these compounds were based on a primary understanding of hAR binding affinity in a biochemical assay, while functional effects were determined based on inhibition of hAR-dependent transcriptional activity in mammalian CV-1 cells. While 8-amino and 8-alkoxy compounds were much weaker antagonists, small electron withdrawing groups at C-8 were preferred, with nitrile (316) and fluorine (317) optimal. In this context, there appears to be a bioisosteric relationship between the C═O, C≡N, and C–F moieties, and the data were proposed to support the concept that a H-bond acceptor is required at this site of the pharmacophore, leading to the suggestion that the active tautomer was that of the pyridone represented in 316 rather than the alternate hydroxy pyridine.(145)

A C–F bond has also been invoked as a C═O isostere in the context of the GABA aminotransferase inhibitors 318 and 319, where the carboxylic acid moiety was mimicked by a 2,6-difluorophenyl ring.(146) The fluorine patterning in 318 and 319, which are competitive inhibitors of GABA aminotransferase with K_i values of 11 and 6.3 mM, respectively, enhanced the acidity of the phenolic hydroxyl, which has a pK_a value of 7.12 compared to 9.81 for phenol. The structural overlays presented in Figure 24 were used to illustrate the postulated isosteric relationship between the C–F bond of 318 and 319 and the C═O moiety of the carboxylic acid of 82.(146)

Figure 24. Structural overlays of 82 with **318** and **319** illustrating C–F and C═O mimicry.

These observations were the basis of the installation of a 2,6-difluorophenol moiety as a potential carboxylic acid bioisostere in a series of carbonic anhydrase inhibitors patterned after the carboxylic acids 320 and 321.(147) In the analysis of the matched pairs 320/321 and 322/323, the 2,6-difluorophenol offered a potency advantage that was further modulated by modifying the phenyl ring substituents of 322 (compounds 324 and 325) or by the introduction of the benzyl moiety, as in 326 and 327.(147)

Alkenyl Fluoride as an Enol Mimetic

Alkenyl fluorides have also been contemplated as mimics of enol-based intermediates in enzyme-mediated reactions.(148−150) The alkenyl fluorides 329 and 330 were prepared as mimics of the (Z) and (E) enol forms, respectively, of pregnenolone 328. These compounds were probed as inhibitors of steroid C_17α hydroxylase/C₁₇₍₂₀₎ lyase, which converts progesterone to androstenedione and 328 to dehydroepiandrostene, with extension to potential therapies for prostate cancer and hormone-dependent breast cancer which rely upon the production of androgens and estrogens, respectively.(148) The enol of 328 is thought to be an intermediate in the initial C_17α hydroxylation step catalyzed by the dual acting enzyme. Incubation of 329 with cynomolgus monkey testicular C₁₇₍₂₀₎ lyase at a concentration of 1 μM resulted in 49% inhibition of enzymatic activity, with the effect determined to be time-dependent because inhibition after 40 min of preincubation increased to 72%. By way of contrast, 330 was associated with 54% inhibition of C₁₇₍₂₀₎ lyase activity at a concentration of 1 μM but with minimal evidence of time-dependence because the amount of inhibition was relatively constant, measured as 60% after a 40 min preincubation period.(148)

Other steroidal enzyme inhibitors where an alkenyl fluoride has been explored as a transition state mimic are the type I and type II 5α-reductases which convert testosterone (331) to the more androgenic dihydrotestosterone (333), with the enolate 332 a postulated intermediate (Scheme 5).(149) Finasteride 18 is a potent inhibitor of the type II 5α-reductase, IC₅₀ = 1.2 nM but is a more modest inhibitor of the type I enzyme IC₅₀ = 650 nM. The alkenyl fluoride 334 inhibited the type II 5α reductase with an IC₅₀ value of 480 nM, 400-fold less potently than 18, and the type I enzyme with an IC₅₀ value of 1300 nM, 2-fold weaker than 18. The alkenyl fluoride 334 was unique in the halogen series because the homologous chloride 335 and bromide 336 were inactive in both assays. In this context, the alkenyl fluoride moiety may be considered reflective of a bioisosteric relationship with both an enolate and an amide.

Scheme 5. Metabolism of **331**–**333** by Steroid 5α-Reductase

The α,β-dihydroxyacid dehydratase class of enzyme catalyzes the elimination of water from a dihydroxy acid to produce the enol 337, which is tautomeric with an α-keto acid, as summarized in Scheme 6.(150) The alkenyl fluoride 338 was prepared as a mimic of 337, a design principle successful to the extent that this compound inhibited the dehydratase with a K_i/K_m ratio of 0.18, superior in this case to the simpler acrylate 339 and the amide 340, which was inactive.

Scheme 6. Reaction Process Catalyzed by α,β-Dihydroxyacid Dehydratase

The 1,1-Difluoro Alkene Moiety as a C═O Bioisostere

The fluorine atoms of the 1,1-difluoroalkene moiety have been advocated in C═O mimesis, with the two fluorine atoms approximating the electron density associated with the lone pairs of electrons associated with the oxygen atom, although with similar dipole alignment of 30% lesser magnitude, as summarized in Figure 25.(151)

Figure 25. Isosteric relationship between formaldehyde and 1,1-difluoroethylene.

A pioneering examination of a 1,1-difluoroalkene as a C═O mimic was in the design of 341 as a substrate analogue of thymidine diphosphate (TDP)-6-desoxy-l-lyxo-4-hexulose (342) which is reduced to TDP-l-rhamnose (343) by the action of TDP-l-rhamnose synthase, a pathway summarized in Scheme 7.(152) The design premise was based on the underlying electronics of the C═CF₂ moiety acting as a C═O mimic, with the anticipation that the addition of hydride to the olefin would occur with facility and in the same fashion as the addition to the ketone carbonyl. This mode of reaction was expected to generate an intermediate anion on a carbon atom that is adjacent to two fluorine atoms, setting up potentially unfavorable interactions with the fluorine lone pairs that would be destabilizing and precipitate either a structural rearrangement or the loss of fluoride to afford a reactive carbene species.(153)

Scheme 7. TDP-l-rhamnose Synthase-Catalyzed Reduction of **342** to **343**

In the event, incubating TDP-l-rhamnose synthase (1 μM) with a 6000-fold excess (6.1 mM) of 341, evaluated as a 3:1 mixture of α- and β-anomers, revealed that it acted as a poor but nevertheless kinetically competent substrate. However, irreversible inactivation of the enzyme was not observed; rather, the isolated products reflected the loss of one (344) or both fluorine atoms (345), an observation that was attributed to hydride addition to the exocyclic carbon atom which was favored over the alternative site of attack (Scheme 8). The resulting anion would be expected to decompose by elimination of fluoride, with the initially produced 344 also acting as a substrate for the enzyme, able to engage in a repeat of the reduction cycle that would lead to the completely defluorinated olefin 345, a process depicted in Scheme 8. Thus, in this context, the difluoro olefin of 341 does indeed act as a mimic of the ketone C═O but reverses the regioselectivity of hydride addition.

Scheme 8. Postulated Reaction Pathway of **341** with TDP-l-rhamnose Synthase

A successful application of the 1,1-difluoroethylene moiety as a bioisostere has been in the design of improved derivatives of the antimalarial agent artemisinin (346) for which resistance is beginning to emerge.(154,155) The difluorinated alkene 347 was conceived as a more stable derivative of the lactone in 346, with in vitro potency improved 2-fold compared to the progenitor.(154) Intraperitoneal (IP) administration of 347 to mice infected with Plasmodium berghei at a dose of 35.5 μmol/kg for 4 days resulted in no detectable parasitemia on day 4 compared to parasitemia levels of 25% for animals dosed with 346 and 50% for the untreated control group.(154b) In this setting, a CF₃-alkene moiety is also an effective carbonyl bioisostere, as demonstrated by the potent in vitro antimalarial activity associated with 348.(154a)

The CF₂ Moiety as a C═O Bioisostere

A CF₂ moiety has been shown to function as an effective ketone bioisostere when installed in analogues of nonimmunosuppressive inhibitors of FK506-binding proteins (FKBPs), members of the immunophilin class of chaperones.(156) The in vitro and in vivo neurotrophic activity exhibited by the immunophilin FK506 (tacrolimus, 349) can be recapitulated by nonimmunosuppressive compounds that mimic the FKBP12-binding portion of the macrolide lactone. The design concept explored initially assessed replacing the ketone carbonyl of the prototype molecule 350 with a CF₂ to afford 351, a compound that performed slightly better as an inhibitor of FKBP12 rotamase activity than the progenitor. The importance of the CF₂ element was underscored by the absence of significant rotamase inhibition by the CH₂ homologue 352. Chemical stability studies indicated that 351 was stable over 27 h in phosphate-buffered saline/DMSO, alleviating concerns around the benzylic difluoride moiety and particularly its relationship with the electron rich aromatic ring. The optimized molecule 354, which was patterned as an analogue of V-10367 (353), inhibited FKBP12 rotamase activity with a K_i of 19 nM, potency that compared favorably with the 0.3 nM K_i observed for 353 under comparable experimental conditions.(156) An X-ray cocrystal structure of 354 bound to FKB12 indicated that one of the fluorine atoms was close to the hydrogen of Tyr₂₆–OH (F to O distance = 3.18 Å), resembling the H-bonding interaction of the ketone C═O of 353, while the second fluorine atom interacted with a meta hydrogen of Phe₃₆ with an aromatic carbon to fluorine distance of 3.02 Å.(156a)

The pyrazolo[4,3-c]pyridine 355 was characterized as a potent γ-secretase inhibitor that was active in vivo in a wild-type FVB mouse model, reducing brain Aβ40 levels by 25% following an oral dose of 5 mg/kg despite the low oral bioavailability (2.5%) of this compound.(157) However, 355 was labile in liver microsomes, with oxidation of both the ethyl substituents and the methylene that is exocyclic to the pyrazole identified as significant sites of metabolic susceptibility. In addition, the pyrazole ring N atom was subject to rapid glucuronidation, while GSH adducts were formed by a process that involved the direct displacement of the chlorine substituent on the phenyl ring.(157) Iterative optimization to address these problems led to the identification of the ketone analogue 356, which was less susceptible to glucuronidation but exhibited poor biological activity in a cell-based assay, despite potent intrinsic enzyme inhibition. This was traced to a chemical degradation pathway that involved elimination of 4-chlorophenylsulfinic acid from these molecules to afford the corresponding hydroxy pyridines 357. Replacing the ketone C═O with a CF₂ gave a series of compounds from which 358 emerged after further structural manipulation designed to more comprehensively address HLM instability. This compound lowered brain Aβ40 by 27% in vivo in a mouse model following oral administration of a dose of 1 mg/kg.(157)

In a series of atypical antipsychotics where the combination of antagonist activity at the dopamine D₂ and serotonin 5HT_2A receptors with agonist effects at the serotonin 5HT_1A receptor was sought, the CF₂ moiety in 360 performed similarly to the ketone 359, an SAR point reproduced in analogues in which the benzothiophene moiety was varied.(158,159)

Fluorinated Motifs as Amide, Sulfonamide, and Urea Mimetics

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Trifluoroethylamine and Difluoroethylamine Derivatives

The bioisosteric relationship between a trifluoroethylamine moiety and an amide functionality was originally conceived by Zanda who examined its potential in the context of designing peptidomimetics (Figure 26).(159,160) In addition, the plasticity of this structural element was recognized based on its potential to be incorporated either in register within the peptide frame, as depicted in Figure 26B, or in the partially retro-inverted configuration illustrated in Figure 26C.

Figure 26. Incorporation of the CF₃CH₂NH motif in a polypeptide backbone in register (B) or in a partially retro-inverted configuration (C) that mimics the amide of a conventional polypeptide (A).

The fundamental basis for mimicry between the CF₃CH₂NH moiety and the more recently explored CHF₂CH₂NH homologue and an amide is captured in Figure 27 and relies upon both geometrical and electronic considerations.(159) The key C–C–N bond angle of the CF₃CH₂NHR moiety is comparable to that of an amide, while the electron withdrawing effects of the CF₃ moiety reduce the basicity of the amine such that the H-bond donating properties of the N–H are more like that of an amide N–H.(159) In addition, the C–F dipoles and electron density are believed to provide some emulation of the amide oxygen lone pairs of electrons. Somewhat analogously, the RCF₂CH₂NH may be viewed as a sulfonamide mimic in which the two fluorine atoms function as metaphors of the sulfone oxygen atoms, with the imprecise topographical relationships between the bonds of the two moieties possibly compensated by the longer C–S and N–S bonds.(159c) These structural elements have the advantage of relieving the topographical constraints imposed by an amide functionality which, in appropriate circumstances, may enhance complementarity with a specific target. While deployment of the CF₃CH₂NH or CHF₂CH₂NH moieties eliminates metabolic sensitivity to amidases, esterases, and proteases, these motifs do introduce a new asymmetric center.

Figure 27. Functional aspects of the mimicry between an amide and a sulfonamide moiety and CF₃CH₂NH and CHF₂CH₂NH.

The CF₃CH₂NH moiety has found application as an amide bioisostere beyond incorporation into peptidomimetics, most prominently in mechanism-based inhibitors of the cathepsin family of cysteine protease inhibitors from which the cathepsin K inhibitor odanacatib (361) was derived.(161) An analysis of the X-ray cocrystal structures of peptide-based inhibitors of cathepsin K revealed that while the P₁–P₂ amide engaged the protein via H-bonding interactions involving both the N–H and C═O oxygen atom, the P₂–P₃ amide element relied upon a H-bond interaction involving only the N–H as a donor.(161a) This inspired the design of trifluoroethylamine derivatives that would reduce the pK_a of the amine while preserving the H-bond donor attributes. The data presented for 362–365 in Table 30 provides key insights into the identification of suitable amide bioisosteres in this series.(161b) The compiled SARs indicate the importance of amine pK_a because the CH₃ analogue 364 is 1000-fold less potent than the CF₃ derivative 362; however, the CF₃CF₂ homologue 363 is somewhat less potent, while the nitrile 365, which has the lowest pK_a within this series, is 30-fold weaker than 362. These results focused attention on the trifluoroethylamine series which was elaborated into the exquisitely potent inhibitor 366, IC₅₀ = 5 pM, a compound that identified the preferred absolute configuration at the trifluoroethylamine asymmetric center because the epimer 367 is almost 1000-fold less potent, IC₅₀ = 4.6 nM.(161) However, the basicity associated with the piperazine moiety of 366 led to its accumulation in acidic lysosomes, rising to concentrations where it was able to inhibit cathepsins B, L, and S despite lower intrinsic inhibitory activity toward these proteases, IC₅₀ values of 111, 47, and 451 nM, respectively. Consequently, the next phase of iterative compound design focused on structural modifications that avoided overt basicity, accomplished initially with the discovery of 368, cathepsin K IC₅₀ = 0.2 nM, that was cocrystallized with the enzyme.(161) The X-ray data confirmed effective amide emulation, with the trifluoroethylamine N–H engaging the carbonyl oxygen atom of Gly₆₆, while the CF₃ moiety projected into bulk solvent. The structural data also confirmed mechanism-based inhibition, with the nitrile moiety of 368 engaging the catalytic cysteine as a covalent iminothioether (Pinner-type) adduct. Further optimization of 368 focused on modulating the PK profile, with the sulfonamide replaced by a methylsulfone and a fluorine introduced to the isoleucine methine carbon atom to block a site of metabolic hydroxylation. A cyclopropyl moiety at P₁ was installed to reduce susceptibility of the amide toward hydrolysis resulting in 361, a potent cathepsin K inhibitor, IC₅₀ = 0.2 nM, that exhibited good selectivity for this enzyme over cathepsins B (IC₅₀ = 1034 nM), L (IC₅₀ = 2295 nM) and S (IC₅₀ = 60 nM).(161c) Although 361 completed advanced clinical trials as a potential treatment for osteoporosis and bone metastasis, increasing bone mineral density and reducing the risk of fractures in patients, the compound was abandoned by its sponsor prior to the filing of an NDA due to the observation of an increased risk for cardiovascular events associated with drug therapy.(161d)

Table 30. SARs Associated with the Series of Cathepsin K Inhibitors 362–365 that Incorporate Potential Amide Bioisosteres at the P₂–P₃ Junction

	R	cathepsin K IC₅₀ (nM)	pK_a
362	CF₃	0.9	1.3
363	CF₂CF₃	2.4	1.8
364	CH₃	988	6.7
365	CN	30	0.7

The high crystallinity associated with 361 resulted in low aqueous solubility, a property that contributed to the low (≤10%) oral bioavailability observed after administration of the drug as a suspension to preclinical species.(162) In an effort to address the dissolution-limited bioavailability, the difluoroethylamine analogue 369 was prepared with the anticipation that the enhanced basicity (pK_a increased by ∼1 unit) would facilitate salt formation with sulfonic acids and HCl and lead to reduced lipophilicity, with Log D decreased from 3.53 for 361 to 0.11 for 369. Compound 369 retained the potent cathepsin K inhibitory activity (IC₅₀ = 1 nM) and protease selectivity associated with 361, while the modified physicochemical properties led to improved oral bioavailability in rats when the compound was administered as a 1% methocel suspension.(162)

A trifluoroethylamine moiety was examined as an amide bioisostere in the design of inhibitors of BACE-1, where a replacement for the anilide in 370 was sought to alleviate concerns about release of the aniline in vivo and its potential to express toxicity after metabolic activation.(164) The drug design process specifically focused on preserving the N–H of the anilide moiety of 370 because this was involved in a critical H-bonding interaction with the C═O oxygen of Gly₂₃₀ of the enzyme based on an X-ray cocrystal structure of a related analogue. It was recognized that the conformational constraint imposed by the planar anilide might be optimized for interaction with Gly₂₃₀ by a benzylamine moiety because it was anticipated to adopt an orthogonal arrangement with respect to the plane of the fluorophenyl ring. Initial derivatization took advantage of a reductive amination protocol to prepare libraries which identified the ethylamine 371 as a modest inhibitor of BACE-1 in a cell-free biochemical assay, IC₅₀ = 13.9 μM. However, 371 was considerably more potent in the cell-based screen, which was attributed to concentration of the basic drug in the acidic endosomal compartment where BACE-1 is located. Consequently, further modification focused on modulation of amine basicity, which was accomplished by fluorination (372–377), as summarized in Table 31. The CF₃-cyclopropane moiety in 377 provided the optimal balance of properties, although further structural manipulation of this chemotype was required in order to surmount a problem associated with problematic CYP 2D6 inhibition. The conformational changes anticipated in the design phase were observed in an X-ray cocrystal structure of 377 with the BACE-1 enzyme, although the compound bound slightly differently in the active site compared to 370 in order to accommodate the altered drug–target vectors. The CF₃ substituent projected into the vestibule of the S₃ pocket, while the cyclopropyl ring filled a lipophilic pocket at the rear of the interface of the S₁ and S₃ pockets. This application provides an illustrative example of the advantage of the CF₃CH₂NH as an amide bioisostere where relief of steric constraint is beneficial.(163)

Table 31. SARs Associated with the BACE-1 Inhibitors 371–377a

^{^a}

*WCA = whole cell assay.

RCF₂CH₂NHR′ as a Bioisostere of RSO₂NHR′

While a bioisosteric relationship between the sulfonamide and RCF₂CH₂NH moieties has not been explicitly recognized, inhibitors of the serine protease thrombin provide an example of the potential for this kind of structural metaphor.(139,159c) The X-ray cocrystal structures of thrombin and factor VIIa inhibitors (Figure 21) indicate that the anilide N–Hs of 378 and its analogues 379–382 engage with the backbone C═O oxygen atom of Gly₂₁₆ in a H-bonding interaction; however, 378 is a modestly potent inhibitor of thrombin with a K_i value of 1.28 μM (Table 32). The difluoroethylamine 379 is 27-fold more potent, while the pyridine analogue 380 adds a further 6-fold potency increase. In this example, fluorination is of importance because the dimethyl and cyclopropyl derivatives 381 and 382, respectively, are several fold less potent.(139a) Interestingly, the fluorine atoms were originally introduced as a means of abrogating metabolic modification at the benzylic site rather than for the purpose of structural emulation.(139d)

Table 32. Structure–Activity Relationships for the Thrombin Inhibitors 378–382

Comparison of the thrombin inhibitory effects expressed by 383 and 384 illustrates a broad-based application of biosisosterism in drug design.(138,139) In these molecules, the oxyguanidine provides a mimetic of the guanidine found in natural substrates but with reduced basicity to facilitate oral delivery, the fluorobenzene ring of 383 can be viewed as a bioisostere of the cyclic amide of 384 while the difluoroethylamine of 383 functions analogously to the sulfonamide of 384.

Fluorinated Amines and Mimesis of Imide-like Motifs

The N-(2,2,2-trifluoroethyl)methanesulfonamide moiety has found application in the optimization of HCV NS4B and acyl-CoA:monoacylglycerol acyltransferase (MGAT) inhibitors.(164,165) Symmetrical monofluorination of each of the CH₃ groups of 385 enhanced potency 3-fold (386), but N-dealkylative metabolism gave difluoroacetone, a compound associated with significant toxicity, while glutathione adducts resulted from oxidative metabolism of the indole heterocycle (Table 33).(164a,b) Pefluorination of a single CH₃ moiety of 385 gave a pair of enantiomers, of which the (S)-isomer 387 was 30-fold more potent than the (R)-isomer 388, while the homologues 389 and 390 were less potent. Further optimization gave 391 as a compound that was advanced into clinical trials.(164c)

Table 33. Structure–activity Relationships Associated with HCV NS4B Inhibitors

The MGAT inhibitor 392 was claimed to express an IC₅₀ value of <12 nM in a biochemical assay and inhibit MGAT expressed in a Caco-2 cell line with an EC₅₀ value of 58 nM, biological effects that translated to a 69% reduction in triacylglycerol absorption in male beagle dogs after an oral dose of 30 mg/kg.(165)

There are several higher homologues of the CF₃CH₂NH moiety that appear to offer opportunity for evaluation as potentially interesting structural metaphors. However, while these have not been the subject of systematic analysis in the context of bioisosteric relationships or the delineation of key physicochemical properties, there are examples of applications scattered throughout the literature in molecules that, in some cases, have been studied in some detail in a preclinical setting. In this section, I highlight representative examples that demonstrate applications in drug design, and which, if applied in an informed fashion in the appropriate context, may offer interesting benefits.

Inhibition of steroid 5α-reductase enzymatic activity has been shown to be sensitive to amide substitution patterns in a series of azasteroid-based inhibitors, particularly with respect to influencing activity toward the type I enzyme that is only modestly inhibited by 18.(166) The introduction of the phenyl ring in dutasteride (393) is associated with potent type I 5α-reductase inhibition that affords a more balanced 5α-reductase inhibitor than 18 (Table 34). The benzylamine derivative 394 exhibits enhanced potency toward the type 1 enzyme compared to 18, which is further enhanced by replacement of the CH₃ with a second CF₃ moiety, as depicted by 395.(167) This modification removes the chirality associated with 394 and would be expected to enhance the H-bond donating capacity of the amide N–H, although in this example the N–H does not appear to be specifically involved in drug–target interactions.(168)

Table 34. Inhibition of Steroid 5α-Reductase Enzyme Activity by Aza Steroid Derivatives 18 and 393–395

	steroid 5α-reductase enzyme inhibition IC₅₀ (nM)
	rat prostate	human prostate	human type I	human type II
18	30/32	52/58	470/313a	8.5/11.3a
393			4b	<0.1b
394	15	16	36	3.3
395	34	20	3.9	1.8

^{^a}

Data taken from 2 independent assays abstracted from different articles.(166,167)

^{^b}

Under the assay conditions used to generate this data, finasteride inhibited the type I and type II enzymes with IC₅₀ values of 150 and 0.18 nM, respectively.(166)

N-CH(CF₃)₂ as a Sulfone Bioisostere

Diarylsulfonylureas, of which sulofenur (396) is the representative prototype, were discovered as cytotoxic antitumor agents using an in vivo screen conducted in mice implanted subcutaneously with solid tumors, a screening approach developed as an alternative to the more traditional approach of in vitro evaluation using hematopoietic tumor-derived cell lines.(169) Clinical toxicity associated with the metabolic release of 4-chloraniline from 396 led to its replacement by LY295501 (397).(170,171) The mode of antitumor action of the sulfonyl ureas is enigmatic but has been attributed, in part, to mitochondrial uncoupling.(170,172) The discovery of 396 stimulated considerable interest in this class of antitumor agent, and one interesting class of cytotoxic agent is provided by 398–400.(173) The mode of action of 398–400 is equally enigmatic, but one interpretation is that they may be related to the sulfonylureas in a fashion that relies upon a bioisosteric relationship between the (CF₃)₂CH and SO₂ moieties. Unfortunately, MMPs are not available that would allow a more precise comparison. However, that the electron withdrawing effects of the two CF₃ substituents influence the proximal urea moiety was indicated by the presence of the isourea tautomer that was observed in polar solvent by ¹H NMR spectroscopic analysis.(173a)

Fluorinated Motifs and Urea Bioisosterism

A careful and detailed theoretical analysis of the isosteric relationship between the urea 401 and fluoro enamide 402 has been conducted that recognizes the close topological similarities depicted in Figure 28.(174) However, while the bond angles and lengths show a close and compelling analogy, only N-alkyl, N-tosyl derivatives were prepared as part of the survey, and although these were shown to be chemically stable under neutral, basic, and acidic conditions, the synthesis of compounds with a free N–H was not described. In addition, there was no discussion of the pK_a value of the N–H in 402 and its homologues. Nevertheless, this motif represents an interesting element for use in drug design, particularly for analogues of ureas that do not possess a free N–H and would thus be more amide-like. However, this moiety has not been adequately explored despite its potential to also be considered as an amide bioisostere, with functional mimicry potentially extending to the CF₃ and CF₂H derivatives 403–405, respectively.

Figure 28. Bond angles and lengths that illustrate topological mimesis between a urea and a fluoroenamide.

In a series of dopamine D₂ partial agonists explored for their potential to treat schizophrenia, the N–H of benzimidazolone of 406 that is distal to the oxyethylamine side chain functioned as a phenol bioisostere.(175) The cyclic urea motif of 406 was effectively mimicked by the 2-trifluoromethyl-substituted benzimidazole 409, which was 24-fold more potent than the methyl homologue 408 and 54-fold more potent than 407, the parent molecule of this series, presumably a reflection on the H-bond donating properties.(175c) Further optimization focused on fused pyran derivatives designed to confer conformational restraint, with both 410 and 411 potent ligands for the high affinity dopamine D₂ receptor.(175a,d) However, in this chemotype, the 2-trifluoromethyl-substituted benzimidazole was a less effective mimic of the urea of 410 and amide of 411, with 15–40-fold lower affinity, for which speculation focused on an effect of ring fusion on the preferred tautomeric state of 412.(175d)

Fluoroamides and Urea Bioisosterism

α-Fluoromethyl and α,α-difluoromethyl secondary amides preferentially adopt a conformation in which the C–F and C═O bonds are aligned in a trans-relationship that is favored by both dipole interactions and reinforced by an electrostatic interaction between the fluorine atom and the amide N–H (Figure 29).(176−178) Indeed, this phenomenon has been exploited to illuminate the topography of the vanilloid receptor (TRPV1) agonist activity of capsaicin (413) by synthesizing and evaluating the α-fluorinated enantiomers 414 and 415.(179) The similar performance of 414 and 415 as agonists at the TRPV1 receptor led to the conclusion that the bound form was the extended conformation depicted in Figure 30A that is accessible to both enantiomers rather than the alternative topography presented in Figure 30B.(179)

Figure 29. Calculated conformational preferences for α-fluoromethyl and α,α-difluoromethyl secondary amides.

Figure 30. Conformational preferences of the α-fluorinated enantiomers of **413** designed to illuminate the bound conformation.

However, there are circumstances where this inherent preference can be overridden in favor of the gauche conformation, which for a simple α-fluoromethyl amide has been calculated to be ∼6 kcal/mol higher in energy than the trans conformer, while for the α,α-difluoromethyl homologue the energy of the conformation that places the C–H and N–H in a syn relationship is ∼4.5 kcal/mol higher (Figure 31).(180) Under these circumstances, α-fluoromethylamides and, particularly, α,α-difluoromethylamides, offer an opportunity to function as urea mimetics, as illustrated by the solid state structure of 416 which crystallizes in the conformation shown, stabilized by close contacts between both the N–H and C–H hydrogen atoms and the pendent carbamate oxygen atom. The bistrifluoromethylamide 417 and monotrifluoromethylamide 418 behave in a similar fashion, with the C–H to oxygen H-bond in 418 shorter than that in 417, reflecting the poorer H-bond donor effects of this motif, anticipated based on the differences in electron withdrawing effects and polarizability.(180a) These molecules adopt conformations comparable to that observed with the thiourea 419, and fluorinated acetanilides have been exploited with some success as organocatalysts based on the anticipation that they would recapitulate the effects of ureas and urea mimics.(180,181) However, the α-fluoro derivatives are more active catalysts than the α,α-difluoro analogues, perhaps surprising based on the calculated H-bond strengths which have been estimated to be ∼3.0 kcal/mol for the α-fluoro derivatives and ∼4.0 kcal/mol for the bis-CF₃ amides, with the latter more capable of overcoming the natural bias toward a conformation in which the F and amide and C═O are in a trans-periplanar arrangement.(181)

Figure 31. Topologies and bond lengths associated with α-fluoro-substituted amides **416**–**418** and urea **419** in the solid state.

These motifs have found only very limited application in drug design presumably a function, in part, of concern for the release of difluoroacetic acid and fluoroacetic acid in vivo. However, an interesting example where the fluorination pattern of an amide moiety exerted an effect on ligand–protein interactions is provided by the disaccharide derivatives 420–423 which bind to the lectin wheat germ agglutinin (WGA), although in this example urea isosterism is not a basis.(182) The mono- and difluoro-acetamides 421 and 422, respectively, bind more tightly to WGA based on NMR analyses than the acetamide 420 and, particularly, the trifluoroacetamide 423. These data were interpreted in the context of a productive C–H to π interaction between a C–H of the acetamide moiety and the phenol ring of a tyrosine residue of WGA. The electron withdrawing effects of fluorine substitution in 421 and particularly 422 polarize the C–H bond, thereby enhancing this interaction. The importance of the effect is underscored by 423, which cannot engage in this kind of interaction and exhibits an order of magnitude lower affinity for WGA than 422.(182)

Halogenated amide analogues of melatonin (424) and agomelatine (426) have revealed interesting structure–activity relationships that indicate the importance of the fluorination pattern on binding affinity (Table 35).(183) The CF₃ amide 429 derived from 426 shows reduced affinity but similar receptor selectivity, while the CH₂F homologue 427 exhibits 10-fold selectivity for the MT₂ receptor subtype. In contrast, the CHF₂ amide is 10-fold selective for MT₁ receptor and retains the potency of 426, a profile analogous to that of the urea 431, while the balanced profile and reduced potency of the CHCl₂ amide 430 illustrates the importance of selecting the correct halogen.(183)

Table 35. Structure–Activity Relationships Associated with Melatonin Agonists

	MT₁ (pK_i)	MT₂ (pK_i)
424	9.34	9.02
425	9.7a
426	∼10	∼10
427	8.21	9.40
428	10.27	9.07
429	8.24	8.75
430	8.30	8.75
431	14.3	7.62

^{^a}

Data from an assay assessing binding to cell membranes using ligands that do not distinguish the receptor subtypes(183a)

C–F as a Carbinol (C–OH) Mimic

ARTICLE SECTIONS

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C–F as a C–OH Bioisostere in Nucleoside Analogues

Replacing the hydroxyl substituents and hydrogen atoms of the ribose ring of nucleosides with fluorine has been extensively explored, with gemcitabine (432), the HBV inhibitor clevudine (433), and the HCV inhibitor sofosbuvir (434), a phosphoramidate prodrug, the most prominent clinically approved fluorinated nucleoside derivatives.(184−187) The introduction of fluorine atoms to the ribose ring has a complex influence on the shape of a nucleoside analogue, with antiperiplanar effects, dipole–dipole, anomeric, and gauche interactions contributing to the overall conformational bias, while interactions between fluorine atoms and a pendent C–H of the ribose or the base can also play a role. Consequently, the outcome is dependent upon the specific topological arrangement of functionality and their stereochemical relationships, with complexity heightened by the potentially selective effect on recognition by kinases and viral polymerases. For example, a 2′-α-fluoro substituent in a 3′-deoxy ribose favors a north conformation of the ribose ring while 2′-β-fluoro substitution prefers the south conformation but less strongly, although this preference can be reinforced by a 3′-α-fluoro substituent (Figure 32). Because HIV-1 reverse transcriptase is believed to recognize nucleotides adopting the south conformation, 2′-α-fluoro substitution leads to inactive antiretroviral agents.(188) This contrasts with the effect of 2′-β-fluoro-substitution on ribose topography, which has been shown to preferentially adopt the south conformation.(189)

Figure 32. Preferred conformation of a 2′-α-fluoro-substituted ribose compared with a 2′-β-fluoro substituted isomer and a 2′-β, 2′-α-difluoro-substituted ribose ring.

The importance of the correct fluorination patterning is most effectively illustrated by the poor HCV inhibitory activity associated with 435, the 2′-β-fluoro analogue of 434.(190) The 2′-fluorine atom of 434 mimics the effects of the 2′-hydroxyl of 436, while 435 mimics that of 437. While conformational preferences may contribute to these observations, specific interactions with the HCV NS5B polymerase also play a role because it is sensitive to the identity of the 2′-α- and 2′-β-substituents, critical ribose recognition elements for Ser₂₈₂ of the enzyme.(187b) While the fluoride of 434 lacks the H-bond donating properties of the hydroxyl of 436 (Figure 33A) and binding leads to a disturbance in the interaction network associated with the 2′-hydoxyl, it appears to be capable of interacting with a side chain N–H of Asn₂₉₁ (Figure 33B), and although the K_m is higher, this nucleotide is able to align correctly for incorporation into the growing RNA chain.(187b)

Figure 33. Key H-bonding interactions between a 2′-methyl ribose moiety (**436**) and the 2′-fluoro-2′-methyl homologue that is the ribose hallmark of **434**.

However, there are limits to the bioisosteric relationship between a 2′-fluoro and a 2′-hydroxyl substituent in the context of RNA. While the use of fluorinated RNA is common in siRNA and aptamers as a means of stabilizing the RNA, incorporation into RNA:DNA hybrids has been found to be poorly efficacious toward activating mammalian RNaseH.(191)

Collagen is the most abundant protein in animals, amounting to ∼30% of the total protein content of humans and ∼75% of the weight of human skin. The polypeptide chains of collagen are comprised of approximately 300 repeats of the triplet sequence XYG in which X is often an l-Pro residue while Y is frequently a 4-(R)-hydroxy-l-proline (438, Hyp) residue.(192) These sequences contribute to both the structure and stability of collagen chains, which adopt tightly wound triple helices that are organized into fibrils conferred with considerable tensile strength. The hydroxyl moiety of Hyp is known to contribute to the properties and stability of collagen but its precise function has been esoteric in nature, initially attributed to either its H-bonding properties or an effect on stabilizing trans-peptide bonds along the backbone. However, studies with 4-fluoroproline (439) as a bioisosteric substitute for the Hyp residue 438 indicate that the predominant effect of 4-substition is to influence the conformation of the pyrrolidine ring of proline, with both the 4-(R)-hydroxy and 4-(R)-fluoro substituents favoring a C^γ-exo conformer as depicted in Figures 5B.(192)

The antibiotic pristinamycin II_B (440), which incorporates d-proline and inhibits protein synthesis by acting on bacterial ribosomes, suffers from dehydration at acidic and basic pH to give a conjugated trienone, which is inactive as an antibacterial agent.(193) To identify structural modifications that would address this problem, reduction of the ketone to an alcohol was explored, with the result that both inhibition in a cell-free translational assay and antibacterial activity were preserved with the (R)-isomer 441 (Table 36). In contrast, the (S)-alcohol 442 was 120-fold less potent in the cell free translation assay and 8-fold less potent as an antibacterial agent. These structure–activity observations were recapitulated with the (R)- and (S)-fluorides 443 and 444, respectively, with the former exhibiting potency similar to 441, while 444 was 10-fold more potent than 442 in the protein translation assay and 4-fold improved in the antibacterial assay.(193)

Table 36. SARs Associated with 440 and Its Analogues

	R	poly(U) IC₅₀ (μM)	MIC (IP8203) (μg/mL)
440	C═O	0.1	4
441	(R)-CHOH	0.05	1
442	(S)-CHOH	6	32
443	(R)-CHF	0.06	0.25
444	(S)-CHF	0.5	8

Fluorinated Motifs and Alcohol/Thiol Bioisosterism

Fluorine has played a role in the design of bioisosteres of alcohols and thiols where the CHF₂ moiety has been exploited as a H-bond donor while replacing a C–OH with a C–F relies upon the ramifications of dipole mimicry.

The intramolecular interaction between the CHF₂ moiety of the pyrazole-based fungicide 445 and the adjacent C═O has been characterized as H-bonding in nature based on IR and ¹H NMR data.(194) The energy of the intramolecular interaction in 445 has been estimated to be ∼1.0 kcal/mol based on a distance of 2.4 Å, which calibrates the CHF₂ moiety as a relatively weak H-bond donor compared to more traditional functionalities which are typically associated with energies of 2–15 kcal/mol. Nevertheless, this interaction appears to be important to the fungicidal activity of 445, which is a consequence of inhibiting fungal succinate dehydrogenase because the CF₃ homologue, which is absent the H-bond donor, exhibits weaker biological effects.(194,195) The 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide moiety is a common structural element in a range of fungicides, including fluxapyroxad (446), sedexane (447), and isopyrazam (448).(195) More recently, intermolecular H-bonds have been observed between the CHF₂ moiety and the nitrile of an adjacent molecule in the single-crystal X-ray structure of the oxadiazole derivative 449, with the key bond angle and length captured in Figure 34.(196)

Figure 34. Intermolecular H-bond observed in the single-crystal X-ray structure of oxadiazole **449**.

Perhaps the most compelling application of the CHF₂ moiety as a H-bond donor is provided by 452, an inhibitor of HCV NS3 protease in which the difluoro-Abu was designed as a mimic of the cysteine residue found at the P₁ site of natural substrates, with the structural similarity illustrated in simplistic fashion in Figure 35.(197a) The design of this compound was inspired by the earlier observations with the pyrazole 445, and 452 was found to be equipotent with the Cys analogue 450, indicative of good functional emulation. Satisfactory bioisosterism was further emphasized by the 20-fold reduced potency observed with the Ala analogue 451, reflecting the importance of the presence of the H-bond donor in 452.

Figure 35. Illustration of the functional mimicry between RSH and RCF₂H in P₁ residues incorporated into **450** and **452**.

The presence of an intermolecular interaction between the CHF₂ moiety and the HCV NS3 protein was confirmed with X-ray cocrystal structures of the smaller inhibitors 453 and 454, both of which formed a mimic of the tetrahedral reaction intermediate by the addition of the catalytic Ser₁₃₉ hydroxyl to the activated carbonyl moiety that is a hallmark of these compounds.(197b) The X-ray structures indicated that the hydrogen atom of the CF₂H element donated a H-bond to the backbone C═O of Lys₁₃₆, while one fluorine atom was close to the C-4 hydrogen atom of the phenyl ring of Phe₁₅₄, suggestive of a weak C–H to fluorine H-bonding interaction. The H-bond lengths measured for the CF₂H moiety were ∼2.57 and ∼2.9 Å, at the upper end of the preferred distance but consistent with the 2.9 Å suggested for C–H to oxygen interactions with aromatic ring donors.(139c,197b)

However, in the X-ray cocrystal structure of the related α-keto acid 455 bound to HCV NS3, the carbon atom of the CHF₂ was found to be 6.28 Å away from the backbone C═O of Lys₁₃₆ and 4.08 Å away from the backbone C═O oxygen atom of Leu₁₃₅.(197c) The 4.08 Å distance represents a C–H to OH-bond that is probably above the preferred limit, so while not ideal, it was nevertheless considered to play a role in drug–target interactions.(139,198) These observations reflect significant differences between this complex and those obtained with 453 and 454 because with 455, the serine hydroxyl approached the activated C═O from the opposite face to that typically observed with serine proteases. This arrangement resulted in the carboxylate moiety rather than the hemiketal oxygen atom occupying the oxyanion hole. The difluoromethyl side chain fitted snugly into the S₁ pocket with one of the fluorine atoms proximal (3.34 Å) to the C-4 hydrogen atom of the thiophene ring, viewed as a form of hydrophobic collapse that may preorient the molecule for presentation to the protease in its extended conformation.

The direct translation of this Cys mimic to the P₁ element of tripeptide-based inhibitors derived from asunaprevir (456) was unsuccessful, with the naturally configured 457 found to be 900-fold less potent in the GT-1a enzyme assay than 456, while the unnatural isomer 458 was a further 2-fold weaker and demonstrated poor inhibition in the GT-1b replicon (Table 37).(199) This SAR point was mirrored by the des-fluoro derivatives 459 and 460, which were poor enzyme inhibitors, observations that demonstrated the importance of the cyclopropane moiety at P₁ of 456. However, replacing the vinyl substituent of 456 with a CHF₂ afforded the potent inhibitor 461, with activity dependent on configuration because 462 was an order of magnitude weaker in the enzyme assay. The unique attributes of the CHF₂ substituent in this setting were underscored by the 10-fold loss in potency observed with the des-fluoro derivative 463 and the fully fluorinated homologue 464, while projecting the CHF₂ moiety further from the core, as in 465, also led to reduced potency. In this analogue, the presence of the fluorine atoms incurred a small but negative impact compared to the simple ethyl derivative 466. An X-ray cocrystal structure of 451 with HCV NS3 protease revealed a close approximation of the hydrogen atom of the CF₂H moiety to the backbone carbonyl of Leu₁₅₅ at a distance that was consistent with a H-bonding interaction.(199)

Table 37. SARs Associated with the HCV NS3 Protease Inhibitors 456–466

The importance of the CHF₂-substituted cyclopropyl moiety identified with 461 in HCV NS3 protease inhibitor design is reflected in the incorporation of this structural element in the potent inhibitors glecaprevir (467) and voxilaprevir (468), both of which express pan-genotypic activity and each of which has been approved for marketing by the FDA as part of a drug combination regimen.(200,201)

Lysophosphatidic acid (LPA) 469 interacts with four GPCR receptors designated as LPA_1–4 and also acts as an agonist for the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ). However, the propensity of LPA to rearrange by acyl migration inspired the design of the difluorinated LPA analogue 470 in which the terminal primary alcohol has been replaced by a difluoromethyl moiety.(202) While 470 failed to interact with LPA_1–3 receptors, this compound stimulated the PPARγ receptor as detected by luciferase expression in CV-1 cells transfected with the enzyme under control of a PPARγ-responsive element, demonstrating the contextual nature of bioisosterism and the limits of functional mimicry.

The bioisosteric relationship between the CHCF₂ and OH moieties has been extended to hydroxamic acids where incorporation of an N–CHCF₂ element functioned as an effective mimic in the context of the 5-lipoxygenase inhibitors 471 and 472.(203)

CF₂ as a Bioisostere of an Oxygen Atom

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CF₂ and Phosphate/Pyrophosphate Mimicry

The CF₂ moiety has been explored extensively as a mimic of an oxygen atom in a variety of structural backgrounds in which the C–F bond is considered to be a mimic of the one of the lone pairs of electrons of oxygen. A seminal example is provided by studies of phosphate chemistry where a phosphonate is frequently employed as a bioisostere. However, this substitution leads to lower acidity compared to a phosphate, which can result in poor functional emulation (Tables 38 and 39). The data compiled in Table 37 illustrates the significant differences between the acid dissociation constants for pyrophosphate (473) and the CH₂ analogue 474.(204,205) While the CCl₂ homologue 475 reduces the pK_a values compared to 474, fluorination offers a superior effect, with the CF₂ derivative 476 the optimal mimic with respect to reproducing the acidity of 473. Indeed, the electron withdrawing properties of fluorine are such that, in this context, monofluoro substitution (474) is as effective at modulating the acidity as two chlorine atoms.

Table 38. pK_a Data for Pyrophosphate (473) and Its Carbon Analogues 474–478

	473	474	475	476	477	478
X	O	CH₂	CCl₂	CF₂	CHF	C(OH)₂
pK_a2	2.36	2.87		<2.6	<2.7
pK_a3	5.77	7.45	6.11	5.80	6.15	5.81
pK_a4	8.22	10.96	9.78	8.00	9.35	8.42

Table 39. pK_a2 Values for a Homologous Series of Phosphonic Acid Derivatives Compared to the Phosphate Phenyl Ester

	PhOP(O)(OH)₂	PhCH₂P(O)(OH)₂	PhCH(F)P(O)(OH)₂	PhCF₂P(O)(OH)₂
pK_a2	6.22	7.72	6.60	5.71

The recognition that the physical properties, bond angles, and bond lengths of difluoromethylenephosphonate render it an effective mimic of phosphate has led to its widespread adoption in the design of inhibitors of phosphatases that are of physiological relevance (Figure 36).(206−208) The synthesis of 479 as a building block for the construction of nonhydrolyzable tyrosine phosphate mimics for use in the design of phosphatase inhibitors was followed by the development of 480 as a mimic of phosphorylated serine, motifs that have been extended to sphingomyelin and other naturally occurring phosphate elements.(209−211)

Figure 36. Geometric parameters for the phosphate, phosphonate, and difluoromethylenephosphonate moieties.

The difluoromethylenephosphonate 481 inhibited PTP1B with an IC₅₀ value of 120 nM, was active in a cell-based assay with an EC₅₀ = 1.2 μM, and exhibited 13% oral bioavailability in the rat, with a C_max of 35 μM, plasma exposure that reduced glucose levels in rat and mouse models after single oral doses of 30 and 10 mg/kg, respectively.(212) The furan carboxylate of 482 was introduced to engage a H₂O molecule observed in the active site of Yersinia pestis outer protein H (YopH) phosphatase, and this compound was a potent inhibitor, IC₅₀ = 190 nM, that reduced intracellular Yersinia pestis replication by 9-fold at 10 μM, a concentration below that where cytotoxicity was seen.(213) The phosphopeptidomimetic 483 targeted the Src homology 2 (SH2) domain of signal transducer and activator of transcription 6 (STAT6) and blocked phosphorylation of Tyr₆₄₁ of STAT6 in intact Beas-2B cells when introduced as its bis-pivaloyloxymethyl prodrug at concentrations of 1–10 μM.(214)

The difluoromethylenephosphonate 485 was designed as an analogue of sphingomyelin (484) that inhibited Bacillus cereus sphingomyelinase with an IC₅₀ value of 57 μM, 2-fold more potent than the des-fluoro analogue.(215)

CF₂ as an Oxygen Bioisostere in Sulfonic Acids and Sulfonamides

The effects of fluorination α- to sulfonic acids and sulfonamides has been examined in the context of inhibition of steroid sulfatases, protein phosphatases, and carbonic anhydrase.(216−220) Steroid sulfatase (STS) catalyzes the hydrolytic desulfation of steroid-based sulfate derivatives to afford the free phenols. Estrogen sulfate (486) and estrone sulfate (487) are substrates for STS, and the former is believed to act as a reservoir for the production of estrogen in breast tumors, suggesting this enzyme as a potential therapeutic target.(217) Sulfonates have been evaluated as STS inhibitors but were poorly active, with 488 representative, K_i = 600 μM.(216a) This was not attributed to an effect on the pK_a relative to the sulfate moiety; rather, the sulfate O atom was considered to be important for interacting with the enzyme. Fluorination of the benzylic carbon atom of 488 gave 489, which was 5-fold more potent and exhibited competitive inhibition kinetics in contrast to the mixed inhibition kinetic profile observed with 488. These potency observations were reproduced in the sulfonamide homologues 490 and 491, where α-fluorination enhanced inhibitory potency by 4-fold, although in this example both compounds exhibited mixed inhibitory kinetics.(216b) Interestingly, the potency of 491 increased with pH, with the K_i value = 28 μM at pH = 8.8 while that of the sulfonate 489 decreased, shifting 2-fold from 73 μM at pH = 7 to 147 μM at pH = 8.8, an observation attributed to the effect of ionization of the sulfonamide.

Difluoromethylsulfonates have also been probed as PTP1B phosphatase inhibitors where α-fluorination resulted in increased potency in two series, as illustrated by comparing data for the MMPs 492/493 and 494/495.(218) Perhaps not surprisingly for a monoionic species, 493 and 495 were less potent PTP1B phosphatase inhibitors than the phosphonate homologues 497 and 499, where α-fluorination also enhanced potency over the unsubstituted compound 496 and 498.(218)

Carbonic anhydrase is a Zn²⁺-dependent enzyme that exhibits affinity for primary sulfonamide moieties which coordinate to the metal.(219) Fluorination α- to the sulfonamide moiety led to a progressive increase in potency, with difluoro(phenyl)methanesulfonamide (502) 10-fold more potent than the prototype 500, while the monofluoro derivative 501 fell between these bookends (Table 40). The effect was more dramatic when comparing the activity of methylsulfonamide 503 with its CF₃ congener 504, where the SARs reflected a close correlation between potency and pK_a value that was consistent with the more potent inhibitors being those more ionized at neutral pH.(220)

Table 40. Carbonic Anhydrase Inhibitor Activity Associated with Sulfonamides 500–504

		IC₅₀ (nM)	pK_a
500	PhCH₂SO₂NH₂	630	10.5
501	PhCHFSO₂NH₂	220	8.8
502	PhCF₂SO₂NH₂	58	7.7
503	CH₃SO₂NH₂	650	10.8
504	CF₃SO₂NH₂	<2	6.3

CF₂ as an Oxygen Bioisostere in Heterocycles

The morpholine heterocycle has long been a staple of drug design when a moderately basic ring system is required because the introduction of the oxygen atom into piperidine reduces the pK_a by 2.6 units compared to piperidine (Table 41).(221) Other electron withdrawing elements that exert a similar effect but offer a range of lipophilicities include sulfur substitution, with thiomorpholine dioxide the most powerful of this series that reduces the pK_a of piperidine by a more substantial 5.7 units.(222−224) Dual fluorination at the 4-position of piperidine modulates the pK_a to the same extent as morpholine but offers ∼2.5 units of increased lipophilicity accompanied by a 70% reduction in PSA, providing a useful heterocycle when physicochemical properties are being optimized. As a consequence, 4,4-difluoropiperidine has been explored extensively by medicinal chemists; however, only a synopsis of the applications is presented in the following section which also highlights examples where biochemical emulation is poor.

Table 41. Experimentally Measured pK_a Values for the Conjugate Acids of a Series of Heterocyclic Amines

The morpholine derivative 505 is a potent inhibitor of the class 3 tyrosine kinase macrophage colony-stimulating factor-1 receptor (FMS) but was poorly stable in HLM, with just 5.2% of the parent remaining after 10 min of incubation.(225) In contrast, the difluoropiperidine analogue 506 fully retained the enzyme inhibitory properties of 505 while offering enhanced metabolic stability in HLM, with 83% of the parent drug remaining intact after 10 min of incubation. A similar relative profile was seen when the compounds were incubated in RLM. In the selective cannabinoid CB₂ agonist series represented by 507–510, the parent piperidine 507 and 4,4-difluorinated homologue 509 offered potency superior to the more polar morpholine 508 and, particularly, the thiomorpholine dioxide 510, a reflection of the lipophilic nature of the receptor binding site.(226) However, while potency increased in parallel with lipophilicity in this series, rat clearance was higher for 507 and 509 compared to 508, while 510 was too weakly active to qualify for testing, indicating a need to carefully balance physicochemical properties.

The 4,4-difluoropiperidine moiety of 512 was an effective replacement for the morpholine heterocycle in 511 in a series of histamine-3 receptor inverse agonists, with both compounds exhibiting comparable affinity for the human receptor.(227) The prototype 511 was also a potent rat H₃ receptor ligand that exhibited high selectivity over the hERG channel (21% inhibition at 10 μM) and CYP inhibition (IC₅₀ > 30 μM) while presenting good metabolic stability in mouse, rat, dog, monkey, and human LMs (t_1/2 > 40 min), high Caco-2 cell permeability, and low plasma protein binding. However, the in vivo clearance of 511 in the rat was very high and the molecule was extensively distributed to tissues, with a high volume of distribution, a large brain to plasma ratio, and an extended brain residence time. The fluorinated piperidine 512 exhibited acceptable metabolic stability in vitro but, unfortunately, exhibited a short 30 min t_1/2 in vivo.

Careful modulation of the pK_a of the SYK inhibitors 513–515 was of importance to the PK profile of these molecules.(228) Although the potency of 515 was an order of magnitude better than the morpholine compound 514 while maintaining mild basicity relative to 513, in this series the morpholine heterocycle ultimately offered the optimal compromise of good oral bioavailability and efficacy in a rat Arthus model. However, 514 was genotoxic in an Ames mutagenicity assay, and 515 proved to be an inadequate substitute because its exposure in vivo was lower than for 514, attributed to higher clearance.

An interesting application of CF₂/O isosterism is provided by the development of the melanin concentrating hormone receptor 1 (MCHR1) inhibitor 518, which was advanced into clinical trials as a phosphate prodrug of the alcohol for the treatment of obesity.(229) While the oxetane 516 showed high plasma exposure in rats following PO dosing, the compound was ineffective at inducing weight loss in a 4 day diet-induced obese (DIO) rat study, attributed to low brain and plasma concentrations at 20 h postdose. Reversion to the cyclobutane analogue 517 as a means of increasing lipophilicity provided an avenue forward but further modification to 518 was required in order to slow metabolism. This compound had adequate metabolic stability in rat LMs and when dosed as the glycine ester prodrug at a dose of 10 mg/kg, high plasma (4.5 μM) and brain (11.3 μM) levels were observed at the 8 h time point, reflecting a brain to plasma ratio of 2.5. Administration of a phosphate prodrug of 518 to DIO rats at a dose of 0.3 mg/kg resulted in a 5% weight loss, and this compound exhibited no evidence of the hepatobiliary lesions that had been seen with earlier compounds in the series when administered daily to rats at doses of up to 100 mg/kg for 30 days.(229)

A CF₂ moiety appears to be an acceptable substitute for ether oxygen atom of the sodium–glucose cotransporter-2 (SGLT₂) inhibitor dapaglifozin (519), with 520 claimed to exhibit a longer duration of glucosuria in vivo in rats.(230a) This work complements studies that successfully replaced the C-4 carbinol of 519 with a gem-fluoromethylene moiety.(231b)

However, there are a number of examples where a gem-difluoromethyl moiety has been found to be an inadequate substitute for a heterocyclic oxygen atom in a biochemical setting. For example, the 4,4-difluoropiperidine 522 derived from 521, an antagonist of the dopamine D₄ receptor, exhibits several-fold lower binding affinity than the morpholine-based prototype.(231) In another example, the morpholine ring of the PI3K α, γ, and δ inhibitor 523 was uniquely active compared to the 4,4-difluoropiperidine analogue 524 and the thiomorpholine dioxide 525.(232)

ArCF₂CH₃ and ArOR Bioisosterism

The difluoroethyl moiety has been advocated as a bioisostere of an aromatic CH₃O substituent based on the structural metaphor depicted in Figure 37, with recognition that the conformational preferences of the two substituents may be quite different, although the difluoroalkyl substituent may be conformationally flexible.(233,234) An example where a 1,1-difluoroethyl substituent offered advantage is found in the series of inhibitors of the kidney urea transporter UT-B represented by 526–529 captured in Table 42.(235) While the OCH₃ derivative 526 exhibited good potency, metabolic stability in rat liver microsomes was very poor and fluorination of the methyl group was not found to be a viable option to solve this problem because 527 suffered a 10-fold loss in potency, although metabolic stability improved dramatically. The ethyl derivative 528 restored potency but metabolic stability was also inadequate, a problem ultimately solved by introducing the 1,1-difluoroethyl substituent, with 529 offering an excellent compromise of targeted properties.

Figure 37. Proposed isosterism between anisole and (1,1-difluoroethyl)benzene.

Table 42. SARs and Metabolic Stability of 526–529, Inhibitors of the Kidney Urea Transporter UT-B

	R	IC₅₀ (nM)	% remaining in RLMs
526	CH₃O	104	6
527	CF₃O	1110	95
528	CH₃CH₂	11	<5
529	CH₃CF₂	14	96

In the series of Takeda G-protein-coupled receptor 5 (TGR5) agonists 530–534 compiled in Table 43, a CF₂CH₃ substituent offered increased metabolic stability in human liver microsomes when paired with the pyridine heterocycle, as configured in 534.(236) The OCH₃ derivative 530 offered poor agonist potency, but this was improved by the introduction of substituents that lowered the constraint toward coplanarity, with OCF₃ (531), CH₂CH₃ (532), and CF₂CH₃ (533) substantially more potent. However, metabolic stability in HLM was an issue for 530–533, solved by the pyridine analogue 534, which has a lower E Log D value, although this was accompanied by some reduction of intrinsic agonist potency. Nevertheless, 531 was the compound selected for more advanced in vivo studies.(236)

Table 43. SARs and Metabolic Stability of TGR5 Agonists 530–534

	R	X	induced human TGR5 EC₅₀ (nM)	CL_int human (μL/min/mg)
530	OCH₃	CH	137	96
531	OCF₃	CH	2.3	184
532	CH₂CH₃	CH	9.2	238
533	CF₂CH₃	CH	2.7	211
534	CF₂CH₃	N	43	18

Fluorinated Alkoxy Moieties and Mimesis

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Conformational Aspects of Fluorinated Alkoxy Moieties

A probe of the CSD confirmed previous literature observations that in the absence of dual ortho substitution, Ar-OCH₃ prefers a coplanar arrangement of the aromatic ring and the O–CH₃ bond favored by ∼3 kcal/mol (Figure 38).(237−239) This is a consequence of rehybridization of the oxygen atom to allow overlap with the unsaturated ring which overcomes allylic 1,3-strain. In contrast, Ar-OCF₃ favors (by ∼0.5 kcal/mol) a conformation in which the O–CF₃ bond is orthogonal to the plane of the aromatic ring, attributed to the reduced electronic overlap between the now electron deficient oxygen atom and the aromatic system that allows allylic 1,3-strain to dominate, furthered by the increased size of fluorine compared to hydrogen. In addition, a hyperconjugative interaction in which one of the lone pairs of electrons on the oxygen atom donates into one of the C–F σ* orbitals is believed to contribute to stabilizing the orthogonal topography. An assessment of the Ar-OCHF₂ substituent revealed no strong preference for a specific conformation although the analysis was based on only 22 examples in the CSD. However, in two cases examined more closely, the C(Ar)–C(Ar)–O–C torsion angle was close to 90°, but the fluorine atoms adopted an endo–exo arrangement in one example and an endo–endo topography in the other. Thus, fluorination of the alkyl moiety of alkyl phenol ethers allows the aryl substituent to function conformationally as mimic of an alkyl substituent.

Figure 38. Conformational aspects of anisole, PhOCF₃, and PhOCHF₂.

Developability Aspects of Fluorinated Alkoxy Moieties

Fluorination of the alkyl moiety of phenol ethers has been explored broadly in drug design, and replacing the OCH₃ of anisole derivatives with an OCF₃ is a common tactic in drug design that is often focused on enhancing metabolic stability based on the premise of mitigating O-demethylation. However, this tactic is not always successful in increasing metabolic stability, dependent upon the potential for alternative sites of metabolism to become a dominant path. This phenomenon has been explored in some detail based on an analysis of MMPs examining the effect of substituting OCH₃ by both OCF₃ and the less common OCHF₂ on metabolic stability, lipophilicity, membrane permeability, and conformation.(237a) The successive replacement of hydrogen by fluorine in anisole leads to a progressive but nonlinear increase in cLog P values, with increments of 0.17, 0.27, and 0.66 for a total of 1.1 log units, accompanied by an increase in MW of 54 for the OCF₃ derivative. Measured Log D values confirmed the increased lipophilicity which ranged from 0.3 to 1.3 units for an OCF₃ for OCH₃ change while an OCHF₂ reduced Log D by 0.3–0.7 log units compared to OCF₃. However, the analysis of 439 MMPs where the only difference was a OCF₃ for OCH₃ substitution indicated that this change had no clear advantage with respect to improving metabolic stability in HLM. Moreover, the analysis revealed a significant difference in favor of OCH₃ (70% of the MMPs) substitution toward improving passive membrane permeability. The comparison of OCHF₂ with OCF₃ was based on 149 MMPs and indicated that although there were compound-specific effects, there was a small overall advantage for OCHF₂. In the membrane permeability assay, a OCHF₂ for OCF₃ substitution showed improved permeability in 67% of cases examined. This was attributed to the OCHF₂ moiety being able to adopt an endo–endo conformation that is similar in lipophilicity to OCF₃, attributed to cancellation of bond polarities, while the endo–exo state is more hydrophilic due to a 3-fold increase in polarity, which may explain the reduced Log D values. In a comparison between OCHF₂ and OCH₃, the former is more lipophilic by 0.2–0.6 log units, and in the HLM MMP analysis, the OCHF₂ substituent showed an advantage over OCH₃ that was statistically significant. However, in the membrane permeability comparison, the OCH₃ derivatives were in general more permeable than their OCHF₂ analogues when the parent molecule fell into the high or low permeability bin, while in the midrange bin, the two moieties were similarly permeable. The conclusion from this study was that OCHF₂ offers advantage over both OCH₃ and OCF₃ during optimization as a means of balancing lipophilicity and molecular weight, conferring improved metabolic stability without compromising membrane permeability.(237a) Nevertheless, there are examples where fluorination of an anisole moiety has a positive effect on metabolic stability, illustrated by comparisons within the series of corticotropin releasing factor-1 (CRF-1) inhibitors 535–538 compiled in Table 44.(240) In this series, replacing the OCH₃ of 535, a site of metabolic lability, with either OCF₃ (536) or OCHF₂ (537), led to reduced intrinsic clearance in HLM although there was sensitivity to the absolute configuration at the cyclopropyl ethyl substituent with the (S)-isomer 538 metabolically less stable.

Table 44. Binding Potency and Metabolic Stability of a Series CRF-1 Inhibitors

	R	CH₃/CF₃ configuration	CRF-1 IC₅₀ (nM)	intrinsic clearance in HLM (mL/min/kg)
535	CH₃	R	1.1	130
536	CF₃	R	6.5	30
537	CHF₂	R	0.46	22
538	CHF₂	S	1.0	62

Fluorination of Alkyl Phenyl Ethers and Conformation

An example where influencing the conformation of an alkyl phenyl ether by fluorination may have played a role in modulating potency is provided by the cholesteryl ester transfer protein (CETP) inhibitors 539 and 540, where the latter is 8-fold more potent than the former.(241) In another example, the SAR associated with the HCV NS4B inhibitors 541–544 suggested that an orthogonal projection of the C-6 substituent was important for HCV GT-1b replicon inhibition because the methoxy derivative 541 was 10-fold less potent than substituents that favor a noncoplanar topography.(164c)

Fluorine As a Nitrile Bioisostere

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The similarity of the biochemical profiles of 316 and 317 provide an example of a bioisosteric relationship between fluorine and the nitrile moiety.(145) Bioisosterism between these substituents has also been proposed in the context of the series of dual 5HT_1A agonists and 5-HT reuptake inhibitors 545–550.(242) An analysis of MEPs and dipole moments of 5-cyano- and 5-fluoro-substituted indoles confirmed the potential for a bioisosteric relationship, with the C–F more similar to a C–CN moiety than a C–Cl bond because the MEP maps and dipole vector for the 5-chloroindole were more similar to the parent. In the event, the fluoro and cyano MMPs 546/548 and 549/550 profiled similarly in the binding and reuptake assays, while the 5-chloro-substituted analogue 547 of 548 was markedly less potent and behaved more like the parent compound 545 in the reuptake inhibition assay.(242) The two benzodioxole analogues 549 and 550 showed similar efficacy in vivo in the ultrasonic vocalization test as a measure of in vivo 5-HT_1A antagonism, and although subsequent studies focused on the nitrile series, the 5-fluoro analogues performed in a very similar fashion where comparisons were made. These studies culminated in the identification of viladozone (551), which was approved as an antidepressant by the FDA in 2011; however, the 5-fluoro analogue 552 presented an analogous profile in a range of assays, confirming the C–F/C–CN isosterism in this context.

The SF₅ Moiety

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DSM-265 (246) is first SF₅-containing drug to enter clinical trials and the in vitro comparison between 246 and 245 suggests a potential bioisosteric relationship between the SF₅ and CF₃ substituents (Table 25). Indeed, the SF₅ moiety has been viewed as a “super CF₃ group”; however, these two substituents are quite different in shape, size, lipophilicity, and electron withdrawing properties, as captured by the data summarized in Table 45.(243,244) The SF₅ substituent is larger in volume than a CF₃ but smaller than a tert-butyl moiety and possesses an octahedral geometry that presents a pyramidal electron density that is quite different from the tetrahedral shape of CF₃, where the electron density is presented as an inverted cone (Figure 39).(243,245) The SF₅ moiety is a more powerful electron withdrawing substituent than CF₃ but similar to SO₂CH₃ and NO₂ and may be considered to be a peripheral member of the family of “superacceptor” substituents that resemble sulfones in which fluorine has a prominent presence, with the key parameters also captured in Table 45.(246) The SF₅ substituent is more lipophilic than either a CH₃SO₂ or a CF₃SO₂ substituent, thereby conferring good membrane permeability while being metabolically stable and chemically robust.

Figure 39. Comparison of the shapes of the CF₃ and SF₅ substituents.

Table 45. Comparison of the Electron Withdrawing (σ_p), Lipophilicity (π), and Substituent Dipole (μ) Values for the tert-Butyl, Nitro, SO₂CH₃, and a Series of Fluorinated Substituents(244)a

^{^a}

*A negative value indicates that the negative end of the dipole vector is toward the substituent.

Medicinal chemistry applications of the SF₅ moiety have largely been limited by a lack of convenient synthetic access to suitable building blocks, but considerable progress has been made toward developing new methodology, and this substituent is beginning to be explored in a variety of settings, although still most typically as a homologue of the CF₃ substituent.(4a,247) In the series of Trypanosoma cruzi trypanothione reductase inhibitors 553–555, the CF₃- and SF₅-substituted compounds 553 and 554, respectively, offered comparable potency and a modest advantage over the tert-butyl derivative 555.(248) However, a kinetic analysis indicated that while 553 was a competitive inhibitor, both 554 and 555 exhibited a mixed competitive–uncompetitive kinetic profile. Compound 554 was docked into the active site of Trypanosoma cruzi trypanothione reductase with the orientation guided by X-ray cocrystal structures obtained with closely related structures, and the key interactions proposed are depicted in Figure 40. The comparable binding affinity of the bulkier inhibitor 554 compared to the smaller CF₃ derivative 553 was attributed to the stronger electron withdrawing nature of the SF₅ substituent that might potentially lead to an increase in the strength of the T-shaped interaction of the attached phenyl ring with the electron-rich Trp₂₁, Tyr₁₁₀, and Met₁₁₃ residues of the enzyme.(248)

Figure 40. Proposed drug–target interactions between **554** and *T. cruzi* trypanothione reductase based on docking of the ligand into the active site of the enzyme.

In the matched pair of cannabinoids 556 and 557, the SF₅ derivative 557 exhibited a modest 2-fold increased potency at CB₁ receptors, while in the thymidine phosphorylase inhibitors 558 and 559, there is a 4-fold advantage for the SF₅ substituent in 559 compared to the CF₃ prototype 558.(249,250) The antidepressant drug fluoxetine (560) is a selective serotonin reuptake inhibitor that also demonstrates affinity for several serotonin receptors.(251) The SF₅-substituted analogue 561 exhibited reduced binding to 5HT_2a and 5HT_2c receptors compared to 560 but had comparable affinity for 5HT_2b receptors. In the case of fenfluramine (562), the SF₅ analogue 563 exhibited 10-fold higher affinity for 5HT_2b and 5HT₆ receptors than the progenitor.(251)

The SF₅ moiety continues to be of contemporary interest as a substituent in drug design with the Mtb inhibitor 565 profiling similarly to the CF₃ analogue 564, although protein binding was higher for the former compound (99.7%) than the latter (99.1%).(252) The oxindole derivatives 566 and 567 have been profiled as kinase inhibitors that express cytotoxicity toward the T47D cancer cell line with EC₅₀ values of 490 and 350 nM, respectively.(253) While modeling studies were utilized in the design of 566 and 567, examples of where the SF₅ substituent confers a specific advantage based on its unique shape and electronic properties remain to be described.

Conclusion

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The unique properties of fluorine continue to reveal itself through the creative application of this unusual element in drug design, with recognition of its potential for mimicking a number of functionalities established as a prominent attribute of this interesting element. The small size of fluorine coupled with the high C–F bond strength has inspired its extensive application as a bioisosteric replacement for the hydrogen atom, particularly with respect to modulating the metabolism and conformation of a molecule. However, the electronic properties of a C–F bond have allowed it to effectively mimic carbonyl, hydroxyl, or nitrile functionality in circumstances that are often very much dependent on context. Thus, specific emulation of these functionalities is often based more on a bioisosteric rather than an isosteric relationship, which can add an element of unpredictability to their application in drug design. The powerful electron withdrawing properties of this electronegative element influence the basicity of proximal amines to an extent that can render an amide mimetic. Moreover, the partial fluorination of methyl groups can lead to polarization of a C–H bond that allows it to function as a H-bond donor that although weaker than more established donors has been shown to be of importance in drug–target interactions. The development of new synthetic methodologies continues to provide facile and effective access to new structural elements containing fluorine that, in turn, are contributing to a deeper understanding of the element and stimulating new applications that often have bioisosterism as an underlying basis. The many examples illustrated in this synopsis reflect the creativity of the medicinal chemistry community at large and anticipate the continued development and application of fluorine in drug design.

Author Information

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Corresponding Author
- Nicholas A. Meanwell - Discovery Chemistry and Molecular Technologies Bristol-Myers Squibb Research and Development P.O. Box 4000, Princeton, New Jersey 08543-4000, United States; http://orcid.org/0000-0002-8857-1515; Email: [email protected]
Notes
The author declares the following competing financial interest(s): I am an employee and shareholder of Bristol-Myers Squibb.

Biography

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Nicholas A. Meanwell

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Nicholas A. Meanwell received his Ph.D. degree from the University of Sheffield and conducted postdoctoral studies at Wayne State University before joining Bristol-Myers Squibb in 1982. He has been associated with the discovery of BMY-433771, an inhibitor of respiratory syncytial virus fusion, the HIV-1 attachment inhibitor prodrug fostemsavir, the HIV-1 maturation inhibitor BMS-955176, and the marketed HCV inhibitors asunaprevir (NS3, Sunvepra), daclatasvir (NS5A, Daklinza), and beclabuvir (NS5B). He is the co-recipient of a 2014 PhRMA Research and Hope Award for Biopharmaceutical Industry Research and a 2017 ACS Heroes of Chemistry Award. He was the recipient of the 2015 Philip S. Portoghese Medicinal Chemistry Lectureship Award and was inducted into the ACS Division of Medicinal Chemistry Hall of Fame in 2015.

Acknowledgments

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I thank Professors Günter Haufe (University Münster) and Frédéric Leroux (University of Strasbourg) for sowing the seeds of this manuscript. Drs. Dinesh Vyas, Kap-Sun Yeung, and Professor Günter Haufe and two reviewers are thanked for their critical review of an early version of the manuscript, while Dr. Makonen Belema is thanked for reviewing all versions of the article.

Abbreviations Used
AML	acute myeloid leukemia
BACE-1	β-site amyloid precursor protein cleaving enzyme 1
BCP	[1.1.1]-bicyclopentane
BTK	Bruton’s tyrosine kinase
Cdk	cyclin-dependent kinase
CETP	cholesteryl ester transfer protein
CFTR	cystic fibrosis transmembrane regulator
CGRP	calcitonin gene-related peptide
CRF-1	corticotropin releasing factor-1
CSD	Cambridge Structural Database
CYP	cytochrome P enzyme
DFT	density functional theory
DHODH	dihydroorotate dehydrogenase
DIO	diet-induced obese
DPP-4	dipeptidyl peptidase-4
ET	endothelin
FAAH	fatty acid amide hydrolase
FAP	fibroblast activation protein
FKBP	FK506-binding protein
FLT3	FMS-like tyrosine kinase 3
F-OPA	fluorinated olefinic peptide nucleic acid
FXa	factor Xa
GABA	γ-aminobutyric acid
GSH	glutathione
hAR	human androgen receptor
hBRS-3	human bombesin receptor subtype-3
HCV	hepatitis C virus
HIV-1	human immunodeficiency virus-1
HLM	human liver microsomes
hPTH	human parathyroid hormone
5-HT	5-hydroxytryptamine (serotonin)
Hyp	4-(R)-hydroxy-l-proline
IDH2	isocitrate dehydrogenase 2
IV	intravenous
LM	liver microsomes
MCHR1	melanin concentrating hormone receptor 1
MEK1	MAP kinase kinase 1
MEP	molecular electrostatic potential
MGAT	acyl-CoA:monoacylglycerol acyltransferase
MI	metabolite intermediate
MMP	matched molecular pairs
Mtb	Mycobacterium tuberculosis
MW	molecular weight
NMDA	N-methyl-d-aspartate
PAMPA	parallel artificial membrane permeability assay
PDB	Protein Data Bank
Pf	Plasmodium falciparum
P-gp	P-glycoprotein
PI3Kα	phosphatidylinositol-3 kinase-α
PNMT	phenylethanolamine N-methyltransferase
PPARγ	peroxisome proliferator-activated receptor-γ
PSA	polar surface area
QM	quantum mechanics
RLM	rat liver microsomes
SAR	structure–activity relationship
STS	steroid sulfatase
TGR5	Takeda G-protein-coupled receptor 5
WGA	wheat germ agglutinin

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This article references 253 other publications.

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A review, with 191 refs., on bioisosteres that incorporates sufficient detail to enable the reader to understand the concepts being delineated. Classical bioisosteres, such as monovalent atoms and groups, divalent isosteres, trivalent atoms and groups, tetra substituted atoms, and ring equiv., and non-classical bioisosteres, such as cyclic vs. non-cyclic non-classical bioisosteric replacements and non-classical bioisosteric replacements of functional groups, are discussed.
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Drug Discovery Today (2006), 11 (7 & 8), 348-354CODEN: DDTOFS; ISSN:1359-6446. (Elsevier)
A review. A survey of novel small-mol. therapeutics reveals that the majority of them result from analog design and that their market value represents two-thirds of all small-mol. sales. In natural science, the term analog, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition implies that the analog of an existing drug mol. shares structural and pharmacol. similarities with the original compd. Formally, this definition allows the establishment of three categories of drug analogs: analogs possessing chem. and pharmacol. similarities (direct analogs); analogs possessing structural similarities only (structural analogs); and chem. different compds. displaying similar pharmacol. properties (functional analogs).
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(e) Lima, L. M.; Barreiro, E. J. Bioisosterism: a useful strategy for molecular modification in drug design. Curr. Med. Chem. 2005, 12, 23– 49, DOI: 10.2174/0929867053363540
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Bioisosterism: A useful strategy for molecular modification and drug design
Lima, Lidia Moreira; Barreiro, Eliezer J.
Current Medicinal Chemistry (2005), 12 (1), 23-49CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)
This review aims to demonstrate the role of bioisosterism in rational drug design as well as in the mol. modification and optimization process aiming to improve pharmacodynamic and pharmacokinetic properties of lead compds.
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1f
Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design
Meanwell, Nicholas A.
Journal of Medicinal Chemistry (2011), 54 (8), 2529-2591CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering phys. properties, reducing or redirecting metab., eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compd. optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examd. are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chem. setting has been adopted by this community.
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(a) Moir, J. Suggestions for a new atomic theory. J. Chem. Metal. Mining Soc. S. Africa 1909, 9 (334–343), 392– 393
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Isomorphism, isosterism and covalence
Langmuir, Irving
Journal of the American Chemical Society (1919), 41 (), 1543-59CODEN: JACSAT; ISSN:0002-7863.
cf. C. A. 3, 1554. In compds. other than those of C the number of electron pairs held in common is not always the same as the number of valence bonds that have usually been assumed; thence it is proposed that the number of pairs of electrons which any atom shares with adjacent atoms be called the covalence of the atom. Pairs of compds. such as CO2 and N2O or CO and N2 which show extraordinary agreement in physical properties and which (according to the octet theory) have the same number and arrangement of electrons in the mol. are called isosteric: compds. or isosteres. The term is applicable not only to mols. but to radicals or groups of atoms which hold pairs of electrons in common. Thus a mol. and an ion may be isosteres, e. g., Ne, Na+ Mg++, Al+++, O- and F- are all isosteric with one another. A table of 21 types of isosterism is given. When isosteric mols. are also isoelectric, that is when they have the same total charge on the comolecule, all of their phys. properties should be closely similar. (Comolecules are groups of atoms held together by pairs of electrons shared by adjacent atoms.) This is shown to be true for cyanate and azide ions and the compds. derived from them. No direct comparison can be made of the phys. properties of isosteres having different electric charges. Thus Na salts do not resemble Ne, although Na+ is isosteric with Ne. But another type of comparison can be made as to the actual isosterism of comolecules with different charges. For example, A and N2 resemble each other closely; therefore chloride ion, isosteric with A, should have a close resemblance to the cyanide ion which is isosteric with N2. The similarity of chlorides and cynides is thus directly correlated with that between A and N. A similar close relationship between K salts and NH4 salts can be derived, since A is an isostere of K+ and CH4 is an isostere of NH4+, while the 2 gases are alike in all their physical properties. Since the Na+ and F- ions are isosteric, while Mg++ and O-- are also isosteric, MgO and NaF should be identical in crystal structure. Both are cubic, and they have the same crystal structure according to the X-ray spectra, except that the atoms are drawn closer together by the greater forces in MgO. Thus they should be looked upon as isomorphous. Other similar pairs are MgF2 and Na2O, KCl and CaS, K2S and CaCl2, Cu2S and ZnCl2, KNO3 and SrCO3, KClO4, and SrSO4, etc. Crystalline form depends on structure as given by the octet theory, which gives a true picture of the constitutions of cryst. solids. The following conclusions are justified: The covalence of Na, K, Cl (in chlorides) is zero; the covalence of the central atom is 4 in nitrates, carbonates, sulfates, perchlorates, phosphates, permanganates, chromates, selenates, arsenates, borofluorides, etc.; carbonates and sulfides are not isomorphous, the covalence of the central atom being 4 and 3, resp.; nitrates and chlorates are not isomorphous, the covalency of the chlorine being 3 in chlorates. The applicability of the octet theory to complex inorg. compds. receives further confirmation by its ability to explain such cases of isomorphism. as between Na2BeF4 and MnCl2.4H2O, K2SO4 and ZnI2.4NH3, K2SnCl4.2H2O and K2FeCl5.H2O, NaAlSi3O8 and CaAl2Si2O8.
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3
Fried, J.; Sabo, E. F. 9α-Fluoro derivatives of cortisone and hydrocortisone. J. Am. Chem. Soc. 1954, 76, 1455– 1456, DOI: 10.1021/ja01634a101
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9α-Fluoro derivatives of cortisone and hydrocortisone
Fried, Josef; Sabo, Emily F.
Journal of the American Chemical Society (1954), 76 (), 1455-6CODEN: JACSAT; ISSN:0002-7863.
cf. C.A. 49, 6298e. 4-Pregnen-9β, 11β-oxido-21-ol-3,20-dione (I) with anhyd. HF in CHCl3 4.5 h. at 0° yielded 50% 9α-fluorohydrocortisone acetate (II), m. 233-4°, [α]D23 123° (c 0.64, CHCl3); II showed 10.7 times the activity of cortisone acetate (III) in the rat-liver glycogen assay. II with MeONa yielded 9α-fluorohydrocortisone (IV), m. 260-2° (decompn.), [α]D23 139° (c 0.55, EtOH). II with chromic acid yielded 9α-fluorocortisone acetate (V), m. 254-5°, [α]D23 155° (c 0.45, CHCl3). Deacetylation of V yielded the alc., m. 261-2°, [α]D23 144° (c 0.41, CHCl3), with 9.0 ± 2.7 times the activity of III. In addn. to II, the reaction of I with HF yielded 10% of an isomer (V), m. 259-62°, [α]D23 272° (c 0.53, EtOH), in which the epoxide group had rearranged to form a double bond and a readily acylatable OH group. V consumed 1 mol of perphthalic acid to give an epoxide, m. 213-14° (decompn.), [α]D23 237° (c 0.59, CHCl3). V with (EtCO)2O and pyridine at room temp. yielded a propionate, m. 261-4°, [α]D22 260° (c 0.40, CHCl3). V with MeSO2Cl in pyridine at 0° yielded a mesylate, m. 151-2° (decompn.), [α]D23 260° (c 0.54, CHCl3).
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(a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 8315– 8359, DOI: 10.1021/acs.jmedchem.5b00258
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Applications of Fluorine in Medicinal Chemistry
Gillis, Eric P.; Eastman, Kyle J.; Hill, Matthew D.; Donnelly, David J.; Meanwell, Nicholas A.
Journal of Medicinal Chemistry (2015), 58 (21), 8315-8359CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review with meta-anal. The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties assocd. with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a mol. can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addn., 18F has been established as a useful positron emitting isotope for use with in vivo imaging technol. that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug mols. and applications in positron emission tomog.
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Journal of Fluorine Chemistry (2014), 167 (), 37-54CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
A review. This review provides a brief assessment of the methodol. field of trifluoromethylation and its possible impact on the development of new CF3-contg. pharmaceuticals. Structural aspects of five new drug-candidates, [tafenoquine (arom. CF3), roniciclib (heteroarom. CF3), BAY-38-7271 (aliph. CF3), sonidegib (O-CF3) and navitoclax (S-CF3)] currently under the development in phase II and III clin. studies, and their biol. properties, therapeutic area and synthesis are critically discussed.
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A review. It has become evident that fluorinated compds. have a remarkable record in medicinal chem. and will play a continuing role in providing lead compds. for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.
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The Many Roles for Fluorine in Medicinal Chemistry
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A review.
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Fluorine in medicinal chemistry
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Chembiochem : a European journal of chemical biology (2004), 5 (5), 637-43 ISSN:1439-4227.
Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.
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Fluorine in Pharmaceuticals: Looking Beyond Intuition
Mueller, Klaus; Faeh, Christoph; Diederich, Francois
Science (Washington, DC, United States) (2007), 317 (5846), 1881-1886CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
A review. Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all phys. and adsorption, distribution, metab., and excretion properties of a lead compd. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on mol. conformation of the drug, has only recently begun. Here, we review exptl. progress in this vein and add complementary anal. based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.
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The role of fluorine in medicinal chemistry
Shah, Poonam; Westwell, Andrew D.
Journal of Enzyme Inhibition and Medicinal Chemistry (2007), 22 (5), 527-540CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)
A review. The small and highly electroneg. fluorine atom can play a remarkable role in medicinal chem. Selective installation of fluorine into a therapeutic or diagnostic small mol. candidate can enhance a no. of pharmacokinetic and physicochem. properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a no. of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomog. (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chem. applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimize mol. properties.
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The importance of fluorine in the life science industry
Maienfisch, Peter; Hall, Roger G.
Chimia (2004), 58 (3), 93-99CODEN: CHIMAD; ISSN:0009-4293. (Swiss Chemical Society)
Fluorine-contg. compds. are at the leading edge of many new developments in the life science industry. In recent years a steady increase in the no. of fluorinated org. mols. reaching com. status as crop protection products and pharmaceutical drugs has been obsd.: in 1978, ∼600 pesticides were known, but only approx. 25 (4%) contained fluorine. Today, fluorine-contg. compds. account for more than 17% of all com. available crop protection agents and many others are currently under development. The structures of the fluorine-contg. development compds. proposed for ISO common names between 1997 and 2002 are highlighted in this paper. In the pharmaceutical area around 220 fluorinated drugs were on the market in 1990, representing ∼8% of all synthetic drugs. Six years later already more than 1500 fluorine-contg. drugs were under development. Fluorine-contg. compds. have also been successful in the market-place, such as the insecticides fipronil and lambda-cyhalothrin, the fungicides epoxiconazole and trifloxystrobin, the herbicides trifluralin and clodinafop, and the pharmaceutical blockbusters Fluoxetine (Prozac), Paroxetine (Paxil), Ciprofloxacin (Cipro) and Cisaprid (Propulsid). This success is mainly due to the fact that selectively fluorinated compds. can exhibit dramatically improved potency when compared to the non-fluorinated analogs. The incorporation of fluorine into a biol. active compd. alters the electronic, lipophilic and steric parameters and can critically increase the intrinsic activity, the chem. and metabolic stability, and the bioavailability. The pos. effects of fluorine on the biol. efficiency is outlined by three examples: in the chem. class of herbicidal thiatriazines, the presence or the absence of fluorine leads to dramatic effects on the biol. activity; the metabolic stability and the pharmacokinetics of aminopyrazinone acetamide thrombin inhibitors were improved by the introduction of fluorine, and in a novel class of insecticides/acaricides any modification of the gem-difluorovinyl group results in a strong decrease of biol. activity.
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5
(a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 2016, 116, 422– 518, DOI: 10.1021/acs.chemrev.5b00392
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Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II-III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas
Zhou, Yu; Wang, Jiang; Gu, Zhanni; Wang, Shuni; Zhu, Wei; Acena, Jose Luis; Soloshonok, Vadim A.; Izawa, Kunisuke; Liu, Hong
Chemical Reviews (Washington, DC, United States) (2016), 116 (2), 422-518CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. We focus herein on a new collection of 51 fluorine-contg. mols. that either were approved after 2011 by the corresponding agencies or still are on clin. development. These compds. cover a large no. of therapeutic areas and, on this occasion, we decided to classify them according to the no. of fluorine atoms or fluorinated moieties. In each case, the structures and modes of action of these new drugs are revised, with a particular focus on the role of fluorine in the biol. and pharmaceutical properties, when appropriate. Finally, representative synthetic routes are highlighted.
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(b) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem. Rev. 2014, 114, 2432– 2506, DOI: 10.1021/cr4002879
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5b
Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001-2011)
Wang, Jiang; Sanchez-Rosello, Maria; Acena, Jose Luis; del Pozo, Carlos; Sorochinsky, Alexander E.; Fustero, Santos; Soloshonok, Vadim A.; Liu, Hong
Chemical Reviews (Washington, DC, United States) (2014), 114 (4), 2432-2506CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A historic review. As expected from the fluorine position on the periodic table of elements, it possesses some extreme properties, in particular, ultimate electronegativity and oxidn. potential. Therefore,elemental fluorine can not be prepd. by chem. reaction, and its isolation in 1886 by Henri Moissan required scientific ingenuity and great personal courage. His historic effort earned him a Noble Prize (1906), and the developed electrolysis method is still in use for industrial prodn. of fluorine gas. However, further development of fluorine chem. was extremely sluggish, pursued by a handful of experts capable of handling the violent gas using specially designed lab. equipment. Industrial-scale prodn. of fluorochems. dates back to late 1930s. Currently, there are about 200 pharmaceuticals containingfluorine, including the 40 new compds. discussed in this review. One may agree that the contribution of the past decade indicates a significant 20% increase in the no. of fluorinated drugs on the market.
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(c) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. Data-mining for sulfur and fluorine: an evaluation of pharmaceuticals to reveal opportunities for drug design and discovery. J. Med. Chem. 2014, 57, 2832– 2842, DOI: 10.1021/jm401375q
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5c
Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery
Ilardi, Elizabeth A.; Vitaku, Edon; Njardarson, Jon T.
Journal of Medicinal Chemistry (2014), 57 (7), 2832-2842CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. Among carbon, hydrogen, oxygen, and nitrogen, sulfur and fluorine are both leading constituents of the pharmaceuticals that comprise our medicinal history. In efforts to stimulate the minds of both the general public and expert scientist, statistics were collected from the trends assocd. with therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new graphical montage compilation: disease focused pharmaceuticals posters. Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronol. and classified according to an assocn. with a particular clin. indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qual. conclusions in this article aim to promote innovative insights into drug development.
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6
(a) Jeschke, P. The unique role of fluorine in the design of active ingredients for modern crop protection. ChemBioChem 2004, 5, 570– 589, DOI: 10.1002/cbic.200300833
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6a
The unique role of fluorine in the design of active ingredients for modern crop protection
Jeschke, Peter
ChemBioChem (2004), 5 (5), 570-589CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The task of inventing and developing active ingredients with useful biol. activities requires a search for novel chem. substructures. This process may trigger the discovery of whole classes of chems. of potential com. interest. Similar biol. effects can often be achieved by completely different compds. However, compds. within a given structural family may exhibit quite different biol. activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compd., its interaction with the active site of the target protein, as well as its physicochem., pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated org. compds. represent an important and growing family of com. agrochems. A no. of recently developed agrochem. candidates represent novel classes of chem. compds. with new modes of action; several of these compds. contain new fluorinated substituents. However, the complex structure-activity relationships assocd. with biol.-active mols. mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a mol. at which fluorine substitution will result in optimal desired effects.
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(b) Jeschke, P. The unique role of halogen substituents in the design of modern agrochemicals. Pest Manage. Sci. 2010, 66, 10– 27, DOI: 10.1002/ps.1829
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6b
The unique role of halogen substituents in the design of modern agrochemicals
Jeschke, Peter
Pest Management Science (2010), 66 (1), 10-27CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)
A review. The past 30 years have witnessed a period of significant expansion in the use of halogenated compds. in the field of agrochem. research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochem. with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, esp. in synthetic methods for particular halogen-substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the no. of com. products contg. mixed' halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addn. to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine-substituted agrochems. throughout the twenty-first century. A no. of these recently developed agrochem. candidates contg. halogen substituents represent novel classes of chem. compds. with new modes of action. However, the complex structure-activity relationships assocd. with biol. active mols. mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a mol. at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilization of halogens and their unique role in the design of modern agrochems., exemplified by various com. products from Bayer CropScience coming from different agrochem. areas. Copyright © 2009 Society of Chem. Industry.
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(c) Fujiwara, T.; O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluorine Chem. 2014, 167, 16– 29, DOI: 10.1016/j.jfluchem.2014.06.014
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6c
Successful fluorine-containing herbicide agrochemicals
Fujiwara, Tomoya; O'Hagan, David
Journal of Fluorine Chemistry (2014), 167 (), 16-29CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
A review. Of the herbicides licensed worldwide, currently around 25% contain at least one fluorine atom and many contain multiple fluorines in the form of difluoro- and trifluoromethyl groups. Fluorine-contg. compds. have made a significant contribution to the development of products for the agrochems. industry and many organofluorine entities have found stable market positions. In this review we highlight the most important fluorinated herbicides in terms of their global use. The compds. are grouped by mode of action. A synthesis route is described for each compd. although the synthesis presented may not actually be the industrial process.
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(d) Jeschke, P. Latest generation of halogen-containing pesticides. Pest Manage. Sci. 2017, 73, 1053– 1056, DOI: 10.1002/ps.4540
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6d
Latest generation of halogen-containing pesticides
Jeschke, Peter
Pest Management Science (2017), 73 (6), 1053-1066CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)
Agriculture is confronted with enormous challenges, from prodn. of enough high-quality food to water use, environmental impacts and issues combined with a continually growing world population. Modern agricultural chem. has to support farmers by providing innovative agrichems., used in applied agriculture. In this context, the introduction of halogen atoms into an active ingredient is still an important tool to modulate the properties of new crop protection compds. Since 2010, around 96% of the launched products (herbicides, fungicides, insecticides/acaricides and nematicides) contain halogen atoms. The launched nematicides contain the largest no. of halogen atoms, followed by insecticides/acaricides, herbicides and fungicides. In this context, fungicides and herbicides contain in most cases fluorine atoms, whereas nematicides and insecticides contain in most cases 'mixed' halogen atoms, for example chlorine and fluorine. This review gives an overview of the latest generation of halogen-contg. pesticides launched over the past 6 years and describes current halogen-contg. development candidates. © 2017 Society of Chem. Industry.
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(a) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem., Int. Ed. 2013, 52, 8214– 8264, DOI: 10.1002/anie.201206566
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7a
Introduction of Fluorine and Fluorine-Containing Functional Groups
Liang, Theresa; Neumann, Constanze N.; Ritter, Tobias
Angewandte Chemie, International Edition (2013), 52 (32), 8214-8264CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.
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(b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and tri-fluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 2015, 115, 826– 870, DOI: 10.1021/cr500277b
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(c) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Functionalization of fluorinated molecules by transition metal-mediated C–F bond activation to access fluorinated building blocks. Chem. Rev. 2015, 115, 931– 972, DOI: 10.1021/cr500257c
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(d) Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V. Polyfluorinated ethanes as versatile fluorinated C2-building blocks for organic synthesis. Chem. Rev. 2015, 115, 973– 1050, DOI: 10.1021/cr500465n
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7d
Polyfluorinated Ethanes as Versatile Fluorinated C2-Building Blocks for Organic Synthesis
Nenajdenko, Valentine G.; Muzalevskiy, Vasiliy M.; Shastin, Aleksey V.
Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 973-1050CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. Prepn. and reactions of polyfluorinated ethanes are addressed. Fluorinated derivs. of alkanes, alkenes, ethers, sulfides, carboxylic acids, sulfinic and sulfonic acids, alcs. and ketones, and arom. and heteroarom. compds. were efficiently prepd. using cheap and available starting materials.
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(e) Yerien, D. E.; Barata-Vallejo, S.; Postigo, A. Difluoromethylation reactions of organic compounds. Chem. - Eur. J. 2017, 23, 14676– 14701, DOI: 10.1002/chem.201702311
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7e
Difluoromethylation Reactions of Organic Compounds
Yerien, Damian E.; Barata-Vallejo, Sebastian; Postigo, Al
Chemistry - A European Journal (2017), 23 (59), 14676-14701CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The difluoromethylation strategies to functionalize different families of org. compds., for the late-stage introduction of a CF2H or CF2Y moieties into org. substrates was presented. These methodologies include, (i) a metal-photoredox catalysis; (ii) transition metal-catalyzed thermal protocols; and (iii) transition-metal-free strategies.
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(a) O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C-F bond. Chem. Soc. Rev. 2008, 37, 308– 319, DOI: 10.1039/B711844A
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8a
Understanding organofluorine chemistry. An introduction to the C-F bond
O'Hagan, David
Chemical Society Reviews (2008), 37 (2), 308-319CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. Fluorine is the most electroneg. element in the periodic table. When bound to carbon it forms the strongest bonds in org. chem. and this makes fluorine substitution attractive for the development of pharmaceuticals and a wide range of specialty materials. Although highly polarized, the C-F bond gains stability from the resultant electrostatic attraction between the polarized Cδ+ and Fδ- atoms. This polarity suppresses lone pair donation from fluorine and in general fluorine is a weak coordinator. However, the C-F bond has interesting properties which can be understood either in terms of electrostatic/dipole interactions or by considering stereoelectronic interactions with neighboring bonds or lone pairs. In this tutorial review these fundamental aspects of the C-F bond are explored to rationalize the geometry, conformation and reactivity of individual organofluorine compds.
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(b) Mikami, K.; Itoh, Y.; Yamanaka, M. Fluorinated carbonyl and olefinic compounds: basic character and asymmetric catalytic reactions. Chem. Rev. 2004, 104, 1– 16, DOI: 10.1021/cr030685w
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8b
Fluorinated Carbonyl and Olefinic Compounds: Basic Character and Asymmetric Catalytic Reactions
Mikami, Koichi; Itoh, Yoshimitsu; Yamanaka, Masahiro
Chemical Reviews (Washington, DC, United States) (2004), 104 (1), 1-16CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review.
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Clark, T.; Murray, J. S.; Lane, P.; Politzer, P. Why are dimethyl sulfoxide and dimethyl sulfone such good solvents?. J. Mol. Model. 2008, 14, 689– 697, DOI: 10.1007/s00894-008-0279-y
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9
Why are dimethyl sulfoxide and dimethyl sulfone such good solvents?
Clark, Timothy; Murray, Jane S.; Lane, Pat; Politzer, Peter
Journal of Molecular Modeling (2008), 14 (8), 689-697CODEN: JMMOFK; ISSN:0948-5023. (Springer GmbH)
The authors carried out B3PW91 and MP2-FC computational studies of DMSO, (CH3)2SO, and di-Me sulfone, (CH3)2SO2. The objective was to establish quant. the basis for their high polarities and b.ps., and their strong solvent powers for a variety of solutes. Natural bond order analyses show that the sulfur-oxygen linkages are not double bonds, as widely believed, but rather are coordinate covalent single S+→O- bonds. The calcd. electrostatic potentials on the mol. surfaces reveal several strongly pos. and neg. sites (the former including σ-holes on the sulfurs) through which a variety of simultaneous intermol. electrostatic interactions can occur. A series of examples is given. In terms of these features the striking properties of DMSO and di-Me sulfone, their large dipole moments and dielec. consts., their high b.ps. and why they are such good solvents, can readily be understood.
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(a) Park, K. B.; Kitteringham, N. R. Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metab. Rev. 1994, 26, 605– 643, DOI: 10.3109/03602539408998319
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10a
Effects of fluorine substitution on drug metabolism: Pharmacological and toxicological implications
Park, B. Kevin; Kitteringham, Neil R.
Drug Metabolism Reviews (1994), 26 (3), 605-43CODEN: DMTRAR; ISSN:0360-2532.
A review with 112 refs. Physicochem. properties of fluorinated drugs, fluorine substitution effect on drug metab., and fluorinated compds. as enzyme inhibitors are discussed.
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(b) Murphy, C. D.; Sandford, G. Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity. Expert Opin. Drug Metab. Toxicol. 2015, 11, 589– 599, DOI: 10.1517/17425255.2015.1020295
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10b
Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity
Murphy, Cormac D.; Sandford, Graham
Expert Opinion on Drug Metabolism & Toxicology (2015), 11 (4), 589-599CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)
A review. Introduction: Fluorine's unique physicochem. properties make it a key element for incorporation into pharmacol. active compds. Its presence in a drug can alter a no. of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. Areas covered: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailability and how the effects obsd. are related to the physicochem. characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biol. systems for fluorinated drug prodn. is discussed. Expert opinion: The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technol. for the manufg. scale and new reagents and methods are required to meet the demands for the prepn. of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to det. the nature of transformation products that may cause ecol. damage.
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11
(a) Meanwell, N. A. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem. Res. Toxicol. 2011, 24, 1420– 1456, DOI: 10.1021/tx200211v
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11a
Improving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and Safety
Meanwell, Nicholas A.
Chemical Research in Toxicology (2011), 24 (9), 1420-1456CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
A review. The development of small mol. drug candidates from the discovery phase to a marketed product continues to be a challenging enterprise with very low success rates that have fostered the perception of poor productivity by the pharmaceutical industry. Although there have been significant advances in preclin. profiling that have improved compd. triaging and altered the underlying reasons for compd. attrition, the failure rates have not appreciably changed. As part of an effort to more deeply understand the reasons for candidate failure, there has been considerable interest in analyzing the physicochem. properties of marketed drugs for the purpose of comparing with drugs in discovery and development as a means capturing recent trends in drug design. The scenario that has emerged is one in which contemporary drug discovery is thought to be focused too heavily on advancing candidates with profiles that are most easily satisfied by mols. with increased mol. wt. and higher overall lipophilicity. The preponderance of mols. expressing these properties is frequently a function of increased arom. ring count when compared with that of the drugs launched in the latter half of the 20th century and may reflect a preoccupation with maximizing target affinity rather than taking a more holistic approach to drug design. These attributes not only present challenges for formulation and absorption but also may influence the manifestation of toxicity during development. By providing some definition around the optimal physicochem. properties assocd. with marketed drugs, guidelines for drug design have been developed that are based largely on calcd. parameters and which may readily be applied by medicinal chemists as an aid to understanding candidate quality. The physicochem. properties of a mol. that are consistent with the potential for good oral absorption were initially defined by Lipinski, with addnl. insights allowing further refinement, while deeper analyses have explored the correlation with metabolic stability and toxicity. These insights have been augmented by careful analyses of physicochem. aspects of drug-target interactions, with thermodn. profiling indicating that the signature of best-in-class drugs is a dependence on enthalpy to drive binding energetics rather than entropy, which is dependent on lipophilicity. Optimization of the entropic contribution to the binding energy of a ligand to its target is generally much easier than refining the enthalpic element. Consequently, in the absence of a fundamental understanding of the thermodn. complexion of an interaction, the design of mols. with increased lipophilicity becomes almost inevitable. The application of ligand efficiency, a measure of affinity per heavy atom, group efficiency, which assesses affinity in the context of structural changes, and lipophilic ligand efficiency, which relates potency to lipophilicity, offer less sophisticated but practically useful anal. algorithms to assess the quality of drug-target interactions. These parameters are readily calcd. and can be applied to lead optimization programs in a fashion that helps to maximize potency while minimizing the kind of lipophilic burden that has been dubbed "mol. obesity". Several recently described lead optimization campaigns provide illustrative, informative, and productive examples of the effect of paying close attention to carefully controlling physicochem. properties by monitoring ligand efficiency and lipophilic ligand efficiency. However, to be successful during the lead optimization phase, drug candidate identification programs will need to adopt a holistic approach that integrates multiple parameters, many of which will have unique dependencies on both the drug target and the specific chemotype under prosecution. Nevertheless, there are many important drug targets that necessitate working in space beyond that which has been defined by the retrospective analyses of marketed drugs and which will require adaptation of some of the guideposts that are useful in directing lead optimization.
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(b) Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 2016, 29, 564– 616, DOI: 10.1021/acs.chemrestox.6b00043
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11b
Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space
Meanwell, Nicholas A.
Chemical Research in Toxicology (2016), 29 (4), 564-616CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The phys., biol., and toxicol. properties of a drug candidate are inextricably linked to its structure, and once a mol. has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biol. properties of a mol. from an anal. of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a mol. is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clin. trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective anal. of drug design practices over the past decade has focused attention on the perception that contemporary mols. are unnecessarily obese, burdened by high mol. wt. and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chem. community with practical guideposts to enhancing compd. quality in the drug design phase and which can readily be applied, a series of efficiency indexes have been proposed that attempt to define aspects of compd. quality in the context of a series of physicochem. parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a mol. on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compd. aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, mols. that fall into space beyond that assocd. with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clin. therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compd. quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success.
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Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455
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12
Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery
Huchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, Klaus
Journal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences.
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Pettersson, M.; Hou, X.; Kuhn, M.; Wager, T. T.; Kauffman, G. W.; Verhoest, P. R. Quantitative assessment of the impact of fluorine substitution on P-glycoprotein (P-gp) mediated efflux, permeability, lipophilicity, and metabolic stability. J. Med. Chem. 2016, 59, 5284– 5296, DOI: 10.1021/acs.jmedchem.6b00027
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Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability
Pettersson, Martin; Hou, Xinjun; Kuhn, Max; Wager, Travis T.; Kauffman, Gregory W.; Verhoest, Patrick R.
Journal of Medicinal Chemistry (2016), 59 (11), 5284-5296CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Mol. wt. (MW) is a key parameter in design, and incorporation of fluorine is assocd. with a disproportionate increase in MW considering the van der Waals radius of fluorine vs. hydrogen. Herein we examine a large compd. data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-cor. mol. wt. (MWFC), where the mol. wt. of fluorine has been subtracted, was found to be a more relevant descriptor.
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Bott, F.; Field, L. D.; Sternhell, S. Steric effects. A study of a rationally designed system. J. Am. Chem. Soc. 1980, 102, 5618– 5626, DOI: 10.1021/ja00537a036
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Steric effects. A study of a rationally designed system
Bott, Garry; Field, Leslie D.; Sternhell, Sever
Journal of the American Chemical Society (1980), 102 (17), 5618-26CODEN: JACSAT; ISSN:0002-7863.
The principles for the rational design of systems suitable for the study of steric effects are defined. A suitable mol. framework [6-(2-X-phenyl)-5-Y-1,1-dimethylindan, I] was synthesized and a study of internal rotation by dynamic NMR spectroscopy (DMNR) of 33 derivs., differing principally in the nature of the mol. fragment (X), showed that (i) for I,( Y = Me; X = halogen) the rotational barriers (ΔG⧧) increase smoothly and monotonically with the van der Waals radius of X (rx), which permits the estn. of effective rx for fragments of lower symmetry. (Ii) the rotational barriers are the sum of additive contributions, designated interference values (IH-X), which can be used to predict the rotational barriers in 2,2'-disubstituted biphenyls. (Iii) a simple geometrical parameter, apparent overlap (r*), which is related to the distortion of the framework in the transition state, is proposed and found to have an excellent linear correlation with the barrier to rotation in 2,2'-disubstituted biphenyls. (I.v.) this correlation can be used for a semiquant. estn. of rotational barriers in biaryls and other systems.
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(a) Lunazzi, L.; Mancinelli, M.; Mazzanti, A.; Lepri, S.; Ruzziconi, R.; Schlosser, M. Rotational barriers of biphenyls having heavy heteroatoms as ortho substituents: experimental and theoretical determination of steric effects. Org. Biomol. Chem. 2012, 10, 1847– 1855, DOI: 10.1039/c1ob06688a
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(b) de Riggi, I.; Virgili, A.; de Moragas, M.; Jaime, C. Restricted rotation and NOE transfer: a conformational study of some substituted (9-anthry1)carbinol derivatives. J. Org. Chem. 1995, 60, 27– 31, DOI: 10.1021/jo00106a010
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(c) Belot, V.; Farran, D.; Jean, M.; Albalat, M.; Vanthuyne, N.; Roussel, C. Steric scale of common substituents from rotational barriers of N-(o-substituted aryl)thiazoline-2-thione atropisomers. J. Org. Chem. 2017, 82, 10188– 10200, DOI: 10.1021/acs.joc.7b01698
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Steric Scale of Common Substituents from Rotational Barriers of N-(o-Substituted aryl)thiazoline-2-thione Atropisomers
Belot, Vincent; Farran, Daniel; Jean, Marion; Albalat, Muriel; Vanthuyne, Nicolas; Roussel, Christian
Journal of Organic Chemistry (2017), 82 (19), 10188-10200CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A steric scale of 20 recurrent groups was established from comparison of rotational barriers on N-(o-substituted aryl)thiazoline-2-thione atropisomers. The resulting energy of activation ΔG⧺rot reflects the spatial requirement of the ortho substituent borne by the aryl moiety, electronic aspects and external parameters (temp. and solvent) generating negligible contributions. Concerning divergent rankings reported in the literature, the great sensitivity of this model allowed us to show unambiguously that a Me appears bigger than a chlorine and gave the following order in size: CN > OMe > OH. For the very bulky CF3 and iPr groups, constraints in the ground state decreased the expected ΔG⧺rot values resulting in a minimization of their apparent sizes.
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(d) Soloshonok, V. A.; Kukhar, V. P.; Galushko, S. V.; Svistunova, N. Y.; Avilov, D. V.; Kuz’mina, N. A.; Raevski, N. I.; Struchkov, Y. T.; Pysarevsky, A. P.; Belokon, Y. N. General method for the synthesis of enantiomerically pure β-hydroxy-α-amino acids, containing fluorine atoms in the side chains. Case of stereochemical distinction between methyl and trifluoromethyl groups. X-ray crystal and molecular structure of the nickel (II) complex of (2S,3S)-2-(trifluoromethyl)threonine. J. Chem. Soc., Perkin Trans. 1 1993, 3143– 3155, DOI: 10.1039/P19930003143
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(e) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P.; Tararov, V. I.; Saveleva, T. F.; Churkina, T. D.; Ikonnikov, N. S.; Kochetkov, K. A.; Orlova, S. A.; Pysarevsky, A. P.; Struchkov, Y. T.; Raevsky, N. I.; Belokon, Y. N. Asymmetric aldol reactions of chiral Ni (II)-complex of glycine with aliphatic aldehydes. Stereodivergent synthesis of syn-(2S)- and syn-(2R)-β-alkylserines. Tetrahedron: Asymmetry 1995, 6, 1741– 1756, DOI: 10.1016/0957-4166(95)00220-J
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(f) Soloshonok, V. A.; Kacharov, A. D.; Avilov, D. V.; Ishikawa, K.; Nagashima, N.; Hayashi, T. Transition metal/base-catalyzed aldol reactions of isocyanoacetic acid derivatives with prochiral ketones, a straightforward approach to stereochemically defined α, α -disubstituted-β-hydroxy-α-amino acids. 1. Scope and limitations. J. Org. Chem. 1997, 62, 3470– 3479, DOI: 10.1021/jo9623402
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Jagodzinska, M.; Huguenot, F.; Candiani, G.; Zanda, M. Assessing the bioisosterism of the trifluoromethyl group with a protease probe. ChemMedChem 2009, 4, 49– 51, DOI: 10.1002/cmdc.200800321
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Assessing the bioisosterism of the trifluoromethyl group with a protease probe
Jagodzinska, Monika; Huguenot, Florent; Candiani, Gabriele; Zanda, Matteo
ChemMedChem (2009), 4 (1), 49-51CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
Prepn. of barbiturates with MMPs inhibiting activities is described.
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Shaughnessy, M. J.; Harsanyi, A.; Li, J.; Bright, T.; Murphy, C. D.; Sandford, G. Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life. ChemMedChem 2014, 9, 733– 736, DOI: 10.1002/cmdc.201300490
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Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S. Metabolism-guided drug design. MedChemComm 2013, 4, 631– 652, DOI: 10.1039/c2md20317k
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Metabolism-guided drug design
Stepan, Antonia F.; Mascitti, Vincent; Beaumont, Kevin; Kalgutkar, Amit S.
MedChemComm (2013), 4 (4), 631-652CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
A review. Preclin. drug metab. studies play a key role in the lead identification and optimization process in drug discovery. Characterization of the metabolic pathways of new chem. entities is an integral part of drug discovery not only in optimizing clearance properties but also in eliminating potential safety concerns assocd. with the formation of protein and/or DNA-reactive metabolites. Metab. studies in early discovery have been used to identify metabolic soft spots leading to high metabolic instability, and also in the characterization of active metabolites. Availability of such information has aided in the rational design of compds. with increased resistance to metab. and overall improvements in oral pharmacokinetics and dose size. Mechanistic drug metab. studies have proven particularly invaluable in mitigating reactive metabolite risks, which can lead to mutagenicity, time-dependent inactivation of cytochrome P 450 enzymes and/or idiosyncratic adverse drug reactions. Characterization of stable conjugates derived from bioactivation of small mol. drug candidates provides indirect information on the structure of the reactive metabolite species, thereby providing insight into the bioactivation mechanism and hence a rationale on which to base subsequent chem. intervention strategies. This review will showcase case studies of metab.-guided drug design using literature and inhouse examples.
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Dossetter, A. G. A matched molecular pair analysis of in vitro human microsomal metabolic stability measurements for methylene substitution or replacements - identification of those transforms more likely to have beneficial effects. MedChemComm 2012, 3, 1518– 1525, DOI: 10.1039/c2md20226c
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(a) Stalford, A. C.; Maggs, J. L.; Gilchrist, T. L.; Park, B. K. The metabolism of 16-fluoroestradiols in vivo: chemical strategies for restricting the oxidative biotransformations of an estrogen receptor imaging agent. Steroids 1997, 62, 750– 776, DOI: 10.1016/S0039-128X(97)00116-5
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(b) Diana, G. D.; Rudewicz, P.; Pevear, D. C.; Nitz, T. J.; Aldous, S. C.; Aldous, D. J.; Robinson, D. T.; Draper, T.; Dutko, F. J.; Aldi, C.; Gendron, G.; Oglesby, R. C.; Volkots, D. L.; Reurnan, M.; Bailey, T. R.; Czerniak, R.; Block, T.; Roland, R.; Oppermand, J. Picornavirus inhibitors: trifluoromethyl substitution provides a global protective effect against hepatic metabolism. J. Med. Chem. 1996, 38, 1355– 1371, DOI: 10.1021/jm00008a014
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(c) DeGoey, D. A.; Chen, H.-J.; Cox, P. B.; Wendt, M. D. Beyond the rule of 5: lessons learned from AbbVie’s drugs and compound collection. J. Med. Chem. 2017, DOI: 10.1021/acs.jmedchem.7b00717
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(a) Ojima, I. Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies. J. Fluorine Chem. 2017, 198, 10– 23, DOI: 10.1016/j.jfluchem.2016.12.016
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21a
Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies
Ojima, Iwao
Journal of Fluorine Chemistry (2017), 198 (), 10-23CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to taxoid anticancer agents and their tumor-targeted drug delivery systems (TTDDSs) for medicinal chem. and chem. biol. studies. Novel 3'-difluorovinyltaxoids were strategically designed to block the metab. by cytochrome P 450, synthesized, and evaluated for their cytotoxicity against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines. 3'-Difluorovinyltaxoids exhibited impressive activities against these cancer cell lines. More significantly, a representative 3'-difluorovinyltaxoid exhibited 230-33,000 times higher potency than conventional anticancer drugs against cancer stem cell-enriched HCT-116 cell line. Studies on the mechanism of action (MOA) of these fluorotaxoids were performed by tubulin polymn. assay, morphol. anal. by electron microscopy (EM) and protein binding assays. Novel 19F NMR probes, BLT-F2 and BLT-S-F6, were designed by strategically incorporating fluorine, CF3 and CF3O groups into tumor-targeting drug conjugates. These 19F-probes were designed and synthesized to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time 19F NMR anal. Time-resolved 19F NMR study on probe BLT-F2 revealed a stepwise mechanism for the release of a fluorotaxoid, which might not be detected by other anal. methods. Probe BLT-S-F6 were very useful to study the stability and reactivity of the drug delivery system in human blood plasma by 19F NMR. The clean anal. of the linker stability and reactivity of drug conjugates in blood plasma by HPLC and 1H NMR is very challenging, but the use of 19F NMR and suitable 19F probes can provide a practical soln. to this problem.
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(b) Kuznetsova, L.; Sun, L.; Chen, J.; Zhao, X.; Seitz, J.; Das, M.; Li, Y.; Veith, J. M.; Pera, P.; Bernacki, R. J.; Xia, S.; Horwitz, S. B.; Ojima, I. Synthesis and biological evaluation of novel 3′-difluorovinyl toxoids. J. Fluorine Chem. 2012, 143, 177– 188, DOI: 10.1016/j.jfluchem.2012.07.007
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21b
Synthesis and biological evaluation of novel 3'-difluorovinyl taxoids
Kuznetsova, Larissa; Sun, Liang; Chen, Jin; Zhao, Xianrui; Seitz, Joshua; Das, Manisha; Li, Yuan; Veith, Jean M.; Pera, Paula; Bernacki, Ralph J.; Xia, Shujun; Horwitz, Susan B.; Ojima, Iwao
Journal of Fluorine Chemistry (2012), 143 (), 177-188CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
A series of 3'-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metab. by cytochrome P 450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3'-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel. Structure-activity relationship study shows the crit. importance of the C2 modifications on the activity against MDR cancer cell line, while the C10 modifications have a rather minor effect on the potency with some exceptions. The effect of the C2 modifications on potency against MCF7 cell line increases in the following order: H < F < Cl < N3. Among the twenty five 3'-difluorovinyl taxoids evaluated, eight taxoids exhibited less than 100 pM IC50 values against MCF7 cell line. Difluorovinyl taxoids induced GTP-independent tubulin polymn. much faster than paclitaxel. Then, the resulting microtubules were stable to Ca2+-induced depolymn., indicating strong stabilization of microtubules. Mol. modeling study indicated that a difluorovinyl taxoid binds to β-tubulin in a manner that is consistent with the REDOR-Taxol structure. The difluorovinyl group appears to mimic the isobutenyl group to some extent, but with very different electronic property, which may account for the unique activities of difluorovinyl taxoids.
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(c) Ehrlichová, M.; Ojima, I.; Chen, J.; Václavíková, R.; Němcová-Fürstová, V.; Vobořilová, J.; Šimek, P.; Horský, S.; Souček, P.; Kovář, J.; Brabec, M.; Gut, I. Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 2012, 385, 1035– 1048, DOI: 10.1007/s00210-012-0785-4
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Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells
Ehrlichova, Marie; Ojima, Iwao; Chen, Jin; Vaclavikova, Radka; Nemcova-Fuerstova, Vlasta; Voborilova, Jana; Simek, Petr; Horsky, Stanislav; Soucek, Pavel; Kovar, Jan; Brabec, Marek; Gut, Ivan
Naunyn-Schmiedeberg's Archives of Pharmacology (2012), 385 (10), 1035-1048CODEN: NSAPCC; ISSN:0028-1298. (Springer)
Resistance of tumors to taxanes causes chemotherapy failure in numerous patients. Resistance is partly due to the low tumor uptake of taxanes and their rapid metab. Structural modifications of taxanes can reduce their P-glycoprotein-related efflux or decrease metab. and consequently increase taxane efficiency. This study compared cytotoxicity and effects of the cell cycle, transport and metab. of novel taxanes SB-T-1102, SB-T-1103, SB-T-1214 and SB-T-1216, fluorinated SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN5109 with paclitaxel in paclitaxel-sensitive (MDA-MB-435) and paclitaxel-resistant (NCI/ADR-RES) human cancer cells. We have shown before that NCI/ADR-RES cells were 1,000-fold less sensitive to paclitaxel than MDA-MB-435 cells in correspondence to P-glycoprotein overexpression and up to 20-fold lower uptake of the drug in the resistant cells. The uptake of novel taxanes was 1.2 to 3.8 times lower than that of paclitaxel in the MDA-MB-435 cells, but 1.5 to 6.5 times higher in NCI/ADR-RES cells. NCI/ADR-RES cells were correspondingly only 2- to 6.6-fold less sensitive than the MDA-MB-435 cells to novel taxanes. Both cell lines showed minimal metab. of the novel taxanes which was therefore not responsible for their different sensitivity, the obsd. differences in their individual efficiency and higher effects than paclitaxel. All novel taxanes caused G2/M block of the cell cycle similar to paclitaxel, but lower at concns. by order of magnitude. Thus, structural modifications of taxanes resulting in their decreased P-glycoprotein-related transport probably caused their higher efficiency than paclitaxel in multidrug-resistant NCI/ADR-RES tumor cells.
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Mascitti, V.; Stevens, B. D.; Choi, C.; McClure, K. F.; Guimarães, C. R. W.; Farley, K. A.; Munchhof, M. J.; Robinson, R. P.; Futatsugi, K.; Lavergne, S. Y.; Lefker, B.; Cornelius, A. P.; Bonin, P. D.; Kalgutkar, A. S.; Sharma, R.; Chen, Y. Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor. Bioorg. Med. Chem. Lett. 2011, 21, 1306– 1309, DOI: 10.1016/j.bmcl.2011.01.088
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Barnes-Seeman, D.; Beck, J.; Springer, C. Fluorinated compounds in medicinal chemistry: recent applications, synthetic advances and matched-pair analysis. Curr. Top. Med. Chem. 2014, 14, 855– 864, DOI: 10.2174/1568026614666140202204242
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Fluorinated Compounds in Medicinal Chemistry: Recent Applications, Synthetic Advances and Matched-Pair Analyses
Barnes-Seeman, David; Beck, Jeremy; Springer, Clayton
Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 14 (7), 855-864CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
A review. In recent years, several new fluorinated functional groups have been employed in medicinal chem. This review will highlight some recent developments in this area. We draw attention to useful synthetic advances for the installation of fluorine-contg. groups. In addn., we examine the application of some fluorinated functional groups that have recently been gaining popularity in drug discovery. We use matched-pair anal. to assemble aggregate data on the impact on potency of one of these groups, pentafluorosulfanyl, as compared to trifluoromethyl. We further used matchedpair anal. to identify some interesting effects on in vitro ADME properties of replacing H by F on certain moieties.
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Barnes-Seeman, D.; Jain, M.; Bell, L.; Ferreira, S.; Cohen, S.; Chen, X.-H.; Amin, J.; Snodgrass, B.; Hatsis, P. Metabolically stable tert-butyl replacement. ACS Med. Chem. Lett. 2013, 4, 514– 516, DOI: 10.1021/ml400045j
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Metabolically Stable tert-Butyl Replacement
Barnes-Seeman, David; Jain, Monish; Bell, Leslie; Ferreira, Suzie; Cohen, Scott; Chen, Xiao-Hui; Amin, Jakal; Snodgrass, Brad; Hatsis, Panos
ACS Medicinal Chemistry Letters (2013), 4 (6), 514-516CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
Susceptibility to metab. is a common issue with the tert-Bu group on compds. of medicinal interest. The authors demonstrate an approach of removing all the fully Sp3 C-Hs from a tert-Bu group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-contg. analogs had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-contg. counterparts.
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Westphal, M. V.; Wolfstädter, B. T.; Plancher, J.-M.; Gatfield, J.; Carreira, E. M. Evaluation of tert-butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities. ChemMedChem 2015, 10, 461– 469, DOI: 10.1002/cmdc.201402502
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Evaluation of tert-Butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities
Westphal, Matthias V.; Wolfstaedter, Bernd T.; Plancher, Jean-Marc; Gatfield, John; Carreira, Erick M.
ChemMedChem (2015), 10 (3), 461-469CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
The tert-Bu group is a common motif in medicinal chem. Its incorporation into bioactive compds. is often accompanied by unwanted property modulation, such as increased lipophilicity and decreased metabolic stability. Several alternative substituents are available for the drug discovery process. Herein, physicochem. data of two series of drug analogs of bosentan and vercirnon are documented as part of a comparative study of tert-Bu, pentafluorosulfanyl, trifluoromethyl, bicyclo[1.1.1]pentyl, and cyclopropyl-trifluoromethyl substituents.
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Chao, Q.; Sprankle, K. G.; Grotzfeld, R. M.; Lai, A. G.; Carter, T. A.; Velasco, A. M.; Gunawardane, R. N.; Cramer, M. D.; Gardner, M. F.; James, J.; Zarrinkar, P. P.; Patel, H. K.; Bhagwat, S. S. Identification of N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo-[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor. J. Med. Chem. 2009, 52, 7808– 7816, DOI: 10.1021/jm9007533
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Sanga, M.; James, J.; Marini, J.; Gammon, G.; Hale, C.; Li, J. An open-label, single-dose, phase I study of the absorption, metabolism, and excretion of quizartinib, a highly selective and potent FLT3 tyrosine kinase inhibitor, in healthy male subjects, for the treatment of acute myeloid leukemia. Xenobiotica 2017, 47, 856– 869, DOI: 10.1080/00498254.2016.1217100
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Liu, G.; Abraham, S.; Liu, X.; Xu, S.; Rooks, A. M.; Nepomuceno, R.; Dao, A.; Brigham, D.; Gitnick, D.; Insko, D. E.; Gardner, M. F.; Zarrinkar, P. P.; Christopher, R.; Belli, B.; Armstrong, R. C.; Holladay, M. W. Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 3436– 3441, DOI: 10.1016/j.bmcl.2015.07.023
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Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors
Liu, Gang; Abraham, Sunny; Liu, Xing; Xu, Shimin; Rooks, Allison M.; Nepomuceno, Ron; Dao, Alan; Brigham, Daniel; Gitnick, Dana; Insko, Darren E.; Gardner, Michael F.; Zarrinkar, Patrick P.; Christopher, Ron; Belli, Barbara; Armstrong, Robert C.; Holladay, Mark W.
Bioorganic & Medicinal Chemistry Letters (2015), 25 (17), 3436-3441CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Based on a putative binding mode of quizartinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clin. development, the authors have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compd. I in tumor xenograft model for further preclin. development.
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Sebhat, I. K.; Franklin, C.; Lo, M. M.-C.; Chen, D.; Jewell, J. P.; Miller, R.; Pang, J.; Palyha, O.; Kan, Y.; Kelly, T. M.; Guan, X.-M.; Marsh, D. J.; Kosinski, J. A.; Metzger, J. M.; Lyons, K.; Dragovic, J.; Guzzo, P. R.; Henderson, A. J.; Reitman, M. L.; Nargund, R. P.; Wyvratt, M. J.; Lin, L. S. Discovery of MK-5046, a potent, selective bombesin receptor subtype-3 agonist for the treatment of obesity. ACS Med. Chem. Lett. 2011, 2, 43– 47, DOI: 10.1021/ml100196d
[ACS Full Text ], [CAS], Google Scholar
29
Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity
Sebhat, Iyassu K.; Franklin, Christopher; Lo, Michael M.-C.; Chen, David; Jewell, James P.; Miller, Randy; Pang, Jianmei; Palyha, Oksana; Kan, Yanqing; Kelly, Theresa M.; Guan, Xiao-Ming; Marsh, Donald J.; Kosinski, Jennifer A.; Metzger, Joseph M.; Lyons, Kathryn; Dragovic, Jasminka; Guzzo, Peter R.; Henderson, Alan J.; Reitman, Marc L.; Nargund, Ravi P.; Wyvratt, Matthew J.; Lin, Linus S.
ACS Medicinal Chemistry Letters (2011), 2 (1), 43-47CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
We report the development and characterization of compd. 22 (MK-5046), a potent, selective small mol. agonist of BRS-3 (bombesin receptor subtype-3). In pharmacol. testing using diet-induced obese mice, compd. 22 caused mechanism-based, dose-dependent redns. in food intake and body wt.
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Furet, P.; Guagnano, V.; Fairhurst, R. A.; Imbach-Weese, P.; Bruce, I.; Knapp, M.; Fritsch, C.; Blasco, F.; Blanz, J.; Aichholz, R.; Hamon, J.; Fabbro, D.; Caravatti, G. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett. 2013, 23, 3741– 3748, DOI: 10.1016/j.bmcl.2013.05.007
[Crossref], [PubMed], [CAS], Google Scholar
30
Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation
Furet, Pascal; Guagnano, Vito; Fairhurst, Robin A.; Imbach-Weese, Patricia; Bruce, Ian; Knapp, Mark; Fritsch, Christine; Blasco, Francesca; Blanz, Joachim; Aichholz, Reiner; Hamon, Jacques; Fabbro, Doriano; Caravatti, Giorgio
Bioorganic & Medicinal Chemistry Letters (2013), 23 (13), 3741-3748CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compds. in inhibiting PI3Kα, a medicinal chem. program has led to the discovery of the clin. candidate NVP-BYL719 I.
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(a) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A survey of the role of noncovalent sulfur interactions in drug design. J. Med. Chem. 2015, 58, 4383– 4438, DOI: 10.1021/jm501853m
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31a
A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design
Beno, Brett R.; Yeung, Kap-Sun; Bartberger, Michael D.; Pennington, Lewis D.; Meanwell, Nicholas A.
Journal of Medicinal Chemistry (2015), 58 (11), 4383-4438CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. Electron deficient, bivalent sulfur atoms have two areas of pos. electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramol. interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a mol. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramol. hydrogen-bonding interaction, appears to be underappreciated by the medicinal chem. community. In this Perspective, we discuss the theor. basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and org. synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermol. interactions between ligand C-S σ* orbitals and proteins are illustrated.
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(b) Zhang, X.; Gong, Z.; Li, J.; Lu, T. Intermolecular sulfur···oxygen interactions: theoretical and statistical investigations. J. Chem. Inf. Model. 2015, 55, 2138– 2153, DOI: 10.1021/acs.jcim.5b00177
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31b
Intermolecular Sulfur···Oxygen Interactions: Theoretical and Statistical Investigations
Zhang, Xuejin; Gong, Zhen; Li, Jian; Lu, Tao
Journal of Chemical Information and Modeling (2015), 55 (10), 2138-2153CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
Intermol. S···O interactions are very common and are important in biol. systems, but until recently, the presence of these contacts in protein-ligand systems largely depended on serendipitous discovery instead of rational design. Here we provide insight into the phenomenon of intermol. S···O contacts by focusing on three sulfur-contg. arom. rings. Quantum mechanics is employed to characterize the strength and directionality of the S···O interactions and to det. their energy dependence on their geometric parameters. Protein Data Bank mining is performed to systematically det. the occurrence and geometry of intermol. S···O interactions, and several representative examples are discussed. Three typical cases are investigated using a combined quantum mechanics/mol. mechanics approach to demonstrate the potential of these interactions in improving binding affinities and physiochem. properties. Overall, our work elucidates the structures and energy features of intermol. S···O interactions and addresses their use in mol. design.
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Rowbottom, M. W.; Faraoni, R.; Chao, Q.; Campbell, B. T.; Lai, A. G.; Setti, E.; Ezawa, M.; Sprankle, K. G.; Abraham, S.; Tran, L.; Struss, B.; Gibney, M.; Armstrong, R. C.; Gunawardane, R. N.; Nepomuceno, R. R.; Valenta, I.; Hua, H.; Gardner, M. F.; Cramer, M. D.; Gitnick, D.; Insko, D. E.; Apuy, J. L.; Jones-Bolin, S.; Ghose, A. K.; Herbertz, T.; Ator, M. A.; Dorsey, B. D.; Ruggeri, B.; Williams, M.; Bhagwat, S.; James, J.; Holladay, M. W. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E. J. Med. Chem. 2012, 55, 1082– 1105, DOI: 10.1021/jm2009925
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Pettersson, M.; Johnson, D. S.; Humphrey, J. M.; Butler, T. W.; am Ende, C. W.; Fish, B. A.; Green, M. E.; Kauffman, G. W.; Mullins, P. B.; O’Donnell, C. J.; Stepan, A. F.; Stiff, C. M.; Subramanyam, C.; Tran, T. P.; Cooper Vetelino, B.; Yang, E.; Xie, L.; Bales, K. R.; Pustilnik, L. R.; Steyn, S. J.; Wood, K. M.; Verhoest, P. R. Design of pyridopyrazine-1,6-dione γ-secretase modulators that align potency, MDR efflux ratio, and metabolic stability. ACS Med. Chem. Lett. 2015, 6, 596– 601, DOI: 10.1021/acsmedchemlett.5b00070
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Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability
Pettersson, Martin; Johnson, Douglas S.; Humphrey, John M.; Butler, Todd W.; am Ende, Christopher W.; Fish, Benjamin A.; Green, Michael E.; Kauffman, Gregory W.; Mullins, Patrick B.; O'Donnell, Christopher J.; Stepan, Antonia F.; Stiff, Cory M.; Subramanyam, Chakrapani; Tran, Tuan P.; Vetelino, Beth Cooper; Yang, Eddie; Xie, Longfei; Bales, Kelly R.; Pustilnik, Leslie R.; Steyn, Stefanus J.; Wood, Kathleen M.; Verhoest, Patrick R.
ACS Medicinal Chemistry Letters (2015), 6 (5), 596-601CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochem. properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp3-character. The lead compd. I (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust redns. of brain Aβ42 and Aβ40 were obsd. in a guinea pig time-course expt.
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Mukherjee, P.; Pettersson, M.; Dutra, J. K.; Xie, L.; am Ende, C. W. Trifluoromethyl oxetanes: synthesis and evaluation as a tert-butyl isostere. ChemMedChem 2017, 12, 1574– 1577, DOI: 10.1002/cmdc.201700333
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34
Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl Isostere
Mukherjee, Paramita; Pettersson, Martin; Dutra, Jason K.; Xie, Longfei; am Ende, Christopher W.
ChemMedChem (2017), 12 (19), 1574-1577CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
The synthesis of new trifluoromethyl oxetanes such as I [R = 4-CO2HC6H4, 2-MeOC6H4CH2, 5-CO2Et-2-thienyl, etc.] was developed using Corey-Chaykovsky epoxidn./ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displayed a broad substrate scope. A limitation to the epoxidn./ring expansion was obsd. when attempting to use a more sterically encumbered aryl trifluoromethyl ketone, the intermediate epoxide, 2-(trifluoromethyl)-2-(2,4,6-trimethylphenyl)oxirane was isolated. The trifluoromethyl oxetane was also evaluated as a tert-Bu isostere in the context of the γ-secretase modulator (GSM) program. The trifluoromethyl oxetane-contg. GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-Bu GSM analog was demonstrated, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-Bu isostere.
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(a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2005, 48, 141– 151, DOI: 10.1021/jm0493156
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35a
(2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
Kim, Dooseop; Wang, Liping; Beconi, Maria; Eiermann, George J.; Fisher, Michael H.; He, Huaibing; Hickey, Gerard J.; Kowalchick, Jennifer E.; Leiting, Barbara; Lyons, Kathryn; Marsilio, Frank; McCann, Margaret E.; Patel, Reshma A.; Petrov, Aleksandr; Scapin, Giovanna; Patel, Sangita B.; Roy, Ranabir Sinha; Wu, Joseph K.; Wyvratt, Matthew J.; Zhang, Bei B.; Zhu, Lan; Thornberry, Nancy A.; Weber, Ann E.
Journal of Medicinal Chemistry (2005), 48 (1), 141-151CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (I) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclin. species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of I, was selected for development as a potential new treatment for type 2 diabetes.
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(b) Kim, D.; Kowalchick, J.E.; Edmondson, S. D.; Mastracchio, A.; Xu, J.; Eiermann, G. J.; Leiting, B.; Wu, J. K.; Pryor, K. D.; Patel, R. A.; He, H.; Lyons, K. A.; Thornberry, N. A.; Weber, A. E. Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate). Bioorg. Med. Chem. Lett. 2007, 17, 3373– 3377, DOI: 10.1016/j.bmcl.2007.03.098
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(c) Thornberry, N. A.; Weber, A. E. Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Curr. Top. Med. Chem. 2007, 7, 557– 568, DOI: 10.2174/156802607780091028
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35c
Discovery of JANUVIA (sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
Thornberry, Nancy A.; Weber, Ann E.
Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2007), 7 (6), 557-568CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
A review. The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclin. validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compds. inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclin. species. Indeed, the obsd. toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chem. efforts focused on identifying a highly selective DPP-4 inhibitor for clin. development. Initial work in an α-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective β-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivs. were prepd., culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclin. species. Optimization of this series led to the discovery of JANUVIA (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.
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Mayer, S. C.; Kreft, A. F.; Harrison, B.; Abou-Gharbia, M.; Antane, M.; Aschmies, S.; Atchison, K.; Chlenov, M.; Cole, D. C.; Comery, T.; Diamantidis, G.; Ellingboe, J.; Fan, K.; Galante, R.; Gonzales, C.; Ho, D. M.; Hoke, M. E.; Hu, Y.; Huryn, D.; Jain, U.; Jin, M.; Kremer, K.; Kubrak, D.; Lin, M.; Lu, P.; Magolda, R.; Martone, R.; Moore, W.; Oganesian, A.; Pangalos, M. N.; Porte, A.; Reinhart, P.; Resnick, L.; Riddell, D. R.; Sonnenberg-Reines, J.; Stock, J. R.; Sun, S.-C.; Wagner, E.; Wang, T.; Woller, K.; Xu, Z.; Zaleska, M. M.; Zeldis, J.; Zhang, M.; Zhou, H.; Jacobsen, J. S. Discovery of begacestat, a notch-1-sparing γ-secretase inhibitor for the treatment of Alzheimer’s disease. J. Med. Chem. 2008, 51, 7348– 7351, DOI: 10.1021/jm801252w
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36
Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease
Mayer, Scott C.; Kreft, Anthony F.; Harrison, Boyd; Abou-Gharbia, Magid; Antane, Madelene; Aschmies, Suzan; Atchison, Kevin; Chlenov, Michael; Cole, Derek C.; Comery, Thomas; Diamantidis, George; Ellingboe, John; Fan, Kristi; Galante, Rocco; Gonzales, Cathleen; Ho, Douglas M.; Hoke, Molly E.; Hu, Yun; Huryn, Donna; Jain, Uday; Jin, Mei; Kremer, Kenneth; Kubrak, Dennis; Lin, Melissa; Lu, Peimin; Magolda, Ron; Martone, Robert; Moore, William; Oganesian, Aram; Pangalos, Menelas N.; Porte, Alex; Reinhart, Peter; Resnick, Lynn; Riddell, David R.; Sonnenberg-Reines, June; Stock, Joseph R.; Sun, Shaiu-Ching; Wagner, Erik; Wang, Ting; Woller, Kevin; Xu, Zheng; Zaleska, Margaret M.; Zeldis, Joseph; Zhang, Minsheng; Zhou, Hua; Jacobsen, J. Steven
Journal of Medicinal Chemistry (2008), 51 (23), 7348-7351CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Aβ in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile Me groups in 9 to trifluoromethyl groups afforded the more stable analog 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.
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Floyd, D. M.; Stein, P.; Wang, Z.; Liu, J.; Castro, S.; Clark, J. A.; Connelly, M.; Zhu, F.; Holbrook, G.; Matheny, A.; Sigal, M. S.; Min, J.; Dhinakaran, R.; Krishnan, S.; Bashyum, S.; Knapp, S.; Guy, R. K. Hit-to-lead studies for the antimalarial tetrahydroisoquinolone carboxanilides. J. Med. Chem. 2016, 59, 7950– 7962, DOI: 10.1021/acs.jmedchem.6b00752
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Selnick, H. G.; Liverton, N. J.; Baldwin, J. J.; Butcher, J. W.; Claremon, D. A.; Elliott, J. M.; Freidinger, R. M.; King, S. A.; Libby, B. E.; McIntyre, C. J.; Pribush, D. A.; Remy, D. C.; Smith, G. R.; Tebben, A. J.; Jurkiewicz, N. K.; Lynch, J. J.; Salata, J. J.; Sanguinetti, M. C.; Siegl, P. K. S.; Slaughter, D. E.; Vyas, K. Class III antiarrhythmic activity in vivo by selective blockade of the slowly activating cardiac delayed rectifier potassium current I_Ks by (R)-2-(2,4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide. J. Med. Chem. 1997, 40, 3865– 3868, DOI: 10.1021/jm970517u
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39
(a) Tohnishi, M.; Nishimatsu, T.; Motoba, K.; Hirooka, T.; Seo, A. Development of a novel insecticide, flubendiamide. J. Pestic. Sci. 2010, 35, 490– 491, DOI: 10.1584/jpestics.J10-06
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39a
Development of a novel insecticide, flubendiamide
Tohnishi, Masanori; Nishimatsu, Tetsuyoshi; Motoba, Kazuhiko; Hirooka, Takashi; Akira, Seo
Journal of Pesticide Science (Tokyo, Japan) (2010), 35 (4), 490-491, 508-515CODEN: JPSTCF; ISSN:1348-589X. (Pesticide Science Society of Japan)
Flubendiamide, a novel class insecticide possessing a unique chem. structure, was discovered by Nihon Nohyaku Co., Ltd., and was registered in Japan in 2007 under the trade name of Phoenix WDG. The compd. is not only the first example of 1,2-benzenedicarboxamide insecticides but also the first practical synthetic insecticide with a mode of action as an activator of ryanodine receptors. It shows high and selective activity against lepidopterous insect pests, which leads to excellent efficacy in the field and excellent safety against non-target organisms, including various beneficial arthropods and natural enemies. These properties suggested the suitability of flubendiamide for integrated pest management (IPM) programs.
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(b) Nakao, T.; Banba, S. Broflanilide: a meta-diamide insecticide with a novel mode of action. Bioorg. Med. Chem. 2016, 24, 372– 377, DOI: 10.1016/j.bmc.2015.08.008
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39b
Broflanilide: A meta-diamide insecticide with a novel mode of action
Nakao, Toshifumi; Banba, Shinichi
Bioorganic & Medicinal Chemistry (2016), 24 (3), 372-377CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
A review. Broflanilide is a meta-diamide [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamide] that exhibits high larvicidal activity against Spodoptera litura. It has been suggested that broflanilide is metabolized to desmethyl-broflanilide and that it acts as a noncompetitive resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor antagonist. The binding site of desmethyl-broflanilide was demonstrated to be distinct from that of conventional noncompetitive antagonists such as fipronil. It has been proposed that the site of action for desmethyl-broflanilide is close to G336 in the M3 region of the Drosophila RDL GABA receptor. However, although the site of action for desmethyl-broflanilide appears to overlap with that of macrocyclic lactones, different modes of actions have been demonstrated for desmethyl-broflanilide and the macrocyclic lactones. The mechanisms underlying the high selectivity of meta-diamides are also discussed in this review. Broflanilide is expected to become a prominent insecticide because it is effective against pests with resistance to cyclodienes and fipronil.
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Swaminathan, S.; Siddiqui, A. U.; Pinkerton, F. D.; Gerst, N.; Wilson, W. K.; Schroepfer, G. J. Inhibitors of sterol synthesis: 3β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5α-cholestan-15-one, an analog of a potent hypocholesterolemic agent in which its major metabolism is blocked. Biochem. Biophys. Res. Commun. 1994, 201, 168– 173, DOI: 10.1006/bbrc.1994.1684
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41
Lepri, S.; Goracci, L.; Valeri, A.; Cruciani, G. Metabolism study and biological evaluation of bosentan derivatives. Eur. J. Med. Chem. 2016, 121, 658– 670, DOI: 10.1016/j.ejmech.2016.06.006
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Metabolism study and biological evaluation of bosentan derivatives
Lepri, Susan; Goracci, Laura; Valeri, Aurora; Cruciani, Gabriele
European Journal of Medicinal Chemistry (2016), 121 (), 658-670CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P 450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogs are often designed to block the major sites of metab. In this paper bosentan analogs were synthesized, and their metab. and biol. activity were evaluated. All synthesized compds. showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
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(a) Thangavelu, B.; Bhansali, P.; Viola, R. E. Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors. Bioorg. Med. Chem. 2015, 23, 6622– 6631, DOI: 10.1016/j.bmc.2015.09.017
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(b) Thangavelu, B.; Mutthamsetty, V.; Wang, Q.; Viola, R. E. Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease. Bioorg. Med. Chem. 2017, 25, 870– 885, DOI: 10.1016/j.bmc.2016.11.060
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42b
Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease
Thangavelu, Bharani; Mutthamsetty, Vinay; Wang, Qinzhe; Viola, Ronald E.
Bioorganic & Medicinal Chemistry (2017), 25 (3), 870-885CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
Canavan disease is a fatal neurol. disorder caused by defects in the metab. of N-acetyl-L-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA obsd. in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-assocd. enzyme responsible for the synthesis of NAA, aspartate N-acetyltransferase (ANAT), has recently been purified and examd. (Wang et al., Prot Expr Purif. 2016;119:11). With the availability, for the first time, of a stable and sol. form of ANAT the authors can now report the identification of initial inhibitors against this biosynthetic enzyme, obtained from the screening of several focused compd. libraries. Two core structures of these moderate binding compds. have subsequently been optimized, with the most potent inhibitors in these series possessing sub-micromolar inhibition consts. (Ki values) against ANAT. Slowing the prodn. of NAA via the inhibition of ANAT will lower the elevated levels of this metabolite and can potentially serve as a treatment option to moderate the symptoms of Canavan disease.
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Kees, K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl)(trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem. 1996, 39, 3920– 3928, DOI: 10.1021/jm960444z
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44
(a) Rose, T. E.; Morisseau, C.; Liu, J.-Y.; Inceoglu, B.; Jones, P. D.; Sanborn, J. R.; Hammock, B. D. 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain. J. Med. Chem. 2010, 53, 7067– 7075, DOI: 10.1021/jm100691c
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44a
1-Aryl-3-(1-acylpiperidin-4-yl)urea Inhibitors of Human and Murine Soluble Epoxide Hydrolase: Structure-Activity Relationships, Pharmacokinetics, and Reduction of Inflammatory Pain
Rose, Tristan E.; Morisseau, Christophe; Liu, Jun-Yan; Inceoglu, Bora; Jones, Paul D.; Sanborn, James R.; Hammock, Bruce D.
Journal of Medicinal Chemistry (2010), 53 (19), 7067-7075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine sol. epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea showed a 7-fold increase in potency, a 65-fold increase in Cmax, and a 3300-fold increase in AUC over its adamantane analog 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea. This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mech. withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.
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(b) Lee, K. S. S.; Liu, J.-Y.; Wagner, K. M.; Pakhomova, S.; Dong, H.; Morisseau, C.; Fu, S. H.; Yang, J.; Wang, P.; Ulu, A.; Mate, C. A.; Nguyen, L. V.; Hwang, S. H.; Edin, M. L.; Mara, A. A.; Wulff, H.; Newcomer, M. E.; Zeldin, D. C.; Hammock, B. D. Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy. J. Med. Chem. 2014, 57, 7016– 7030, DOI: 10.1021/jm500694p
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44b
Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy
Lee, Kin Sing Stephen; Liu, Jun-Yan; Wagner, Karen M.; Pakhomova, Svetlana; Dong, Hua; Morisseau, Christophe; Fu, Samuel H.; Yang, Jun; Wang, Peng; Ulu, Arzu; Mate, Christina A.; Nguyen, Long V.; Hwang, Sung Hee; Edin, Matthew L.; Mara, Alexandria A.; Wulff, Heike; Newcomer, Marcia E.; Zeldin, Darryl C.; Hammock, Bruce D.
Journal of Medicinal Chemistry (2014), 57 (16), 7016-7030CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of sol. epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, the authors describe a series of newly synthesized sEH inhibitors I [R1 = 4-CF3C6H4, 4-CF3OC6H4; (CF3)2CFC6H4, etc.; R2 = MeCO, MeCH2CO, MeCH2CH2CO, etc.] with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better phys. properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
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Atouioual, B.; Hagmann, L.; Jung, P. M. J.; Lamy, E.; Winkler, T. Atropisomerism about a heptafluoroisopropyl to aryl bond in 5-amino-4-heptafluoroisopropyl indazole. Tetrahedron Lett. 2008, 49, 5403– 5404, DOI: 10.1016/j.tetlet.2008.07.006
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46
(a) Dieckhaus, C. M.; Thompson, C. D.; Roller, S. G.; Macdonald, T. L. Mechanisms of idiosyncratic drug reactions: the case of felbamate. Chem.-Biol. Interact. 2002, 142, 99– 117, DOI: 10.1016/S0009-2797(02)00057-1
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46a
Mechanisms of idiosyncratic drug reactions: the case of Felbamate
Dieckhaus, Christine M.; Thompson, Charles D.; Roller, Shane G.; MacDonald, Timothy L.
Chemico-Biological Interactions (2002), 142 (1-2), 99-117CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)
A review. Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence, and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicol. outcome. As the name implies, IDR are unpredictable and often result in the post-marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include Trovafloxacin, Zileuton, Troglitazone, Tolcapone, and Felbamate. To date there exists no pre-clin. model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, the authors have studied the IDR assocd. with a model compd., Felbamate. The studies with Felbamate are consistent with the theory that compds. which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In addn., the data suggest that under normal physiol. conditions glutathione plays a protective role in preventing IDR during Felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clin. studies with Felbamate have been able to demonstrate an assocn. between reactive metabolite formation and a clin. relevant toxicity; however, addnl. research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.
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(b) Kapetanovic, I. M.; Torchin, C. D.; Strong, J. M.; Yonekawa, W. D.; Lu, C.; Li, A. P.; Dieckhaus, C. M.; Santos, W. L.; Macdonald, T. L.; Sofia, R. D.; Kupferberg, H. J. Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro. Chem.-Biol. Interact. 2002, 142, 119– 134, DOI: 10.1016/S0009-2797(02)00058-3
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46b
Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro
Kapetanovic, Izet M.; Torchin, Cynthia D.; Strong, John M.; Yonekawa, Wayne D.; Lu, Chuang; Li, Albert P.; Dieckhaus, Christine M.; Santos, Webster L.; MacDonald, Timothy L.; Sofia, R. Duane; Kupferberg, Harvey J.
Chemico-Biological Interactions (2002), 142 (1-2), 119-134CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)
Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia assocd. with its use. It was proposed that a bioactivation of FBM leading to formation of α,β-unsatd. aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities assocd. with the parent drug. Other members of this class of compds., acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examd. effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metab. and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metab. of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concns. of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as obsd. with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metab. and/or metab. of other endogenous or exogenous compds. and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with crit. cellular macromols. or indirect interference with cellular detoxification mechanisms.
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(c) Popović, M.; Nierkens, S.; Pieters, R.; Uetrecht, J. Investigating the role of 2-phenylpropenal in felbamate-induced idiosyncratic drug reactions. Chem. Res. Toxicol. 2004, 17, 1568– 1576, DOI: 10.1021/tx0498197
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Parker, R. J.; Hartman, N. R.; Roecklein, B. A.; Mortko, H.; Kupferberg, H. J.; Stables, J.; Strong, J. M. Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by post-mitochondrial suspensions. Chem. Res. Toxicol. 2005, 18, 1842– 1848, DOI: 10.1021/tx050130r
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48
(a) Kupferberg, H. J.; Macdonald, T. L.; Dieckhaus, C. M.; Perhach, J. L.; Sofia, R. D. Fluorofelbamate: pharmacodynamic and metabolic profile of a potent anticonvulsant. Epilepsia 2000, 41 (Suppl 7), 214
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(b) Mazarati, A. M.; Sofia, R. D.; Wasterlain, C. G. Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus. Seizure 2002, 11, 423– 430, DOI: 10.1053/seiz.2002.0677
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48b
Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus
Mazarati Andrey M; Sofia R Duane; Wasterlain Claude G
Seizure (2002), 11 (7), 423-30 ISSN:1059-1311.
PURPOSE: To examine the seizure-protective properties of fluorofelbamate, a felbamate analog, on acute and chronic seizures in an experimental model of self-sustaining status epilepticus (SSSE). METHODS: SSSE was induced by stimulation of the perforant path for 30 min (PPS) through chronically implanted electrodes in free-running adult male Wistar rats. Fluorofelbamate was injected intravenously (i.v.) either 10 min, or 40 min after SSSE induction. Seizure and spike profiles were analyzed off-line. RESULTS: Fluorofelbamate injected during the early stages of SSSE (10 min after the end of PPS), shortened the duration of seizures in a dose-dependent manner. While a dose of 50 mg kg(-1) was ineffective, 100 and 200 mg kg(-1) reduced cumulative seizure time from 393 +/- 10 min to 15 +/- 8 min and 2.4 +/- 0.5 min respectively. Administration of fluorofelbamate (200 and 300 mg kg (-1)) at a late stage of SSSE, which is refractory to treatment with conventional anticonvulsants, also significantly attenuated seizures. Acute fluorofelbamate treatment (200 mg kg(-1) 10 min after PPS) significantly decreased the frequency of spontaneous seizures which follow SSSE after a 'latent' interval. Moreover, in contrast to control animals, fluorofelbamate-treated rats showed regression of spontaneous seizures, and an apparent remission of epilepsy within 2 months after SSSE. CONCLUSIONS: Acute treatment of SSSE with fluorofelbamate showed strong anticonvulsant effects even during the late stages of SSSE. In this model, it also displayed antiepileptogenic properties: it reduced the severity of chronic epilepsy after SSSE and lead to apparent remissions of that epilepsy.
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(a) Roecklein, B. A.; Sacks, H. J.; Mortko, H.; Stables, J. Fluorofelbamate. Neurotherapeutics 2007, 4, 97– 101, DOI: 10.1016/j.nurt.2006.11.015
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49a
Fluoro0felbamate
Roecklein, Bryan A.; Sacks, Harry J.; Mortko, Henry; Stables, James
Neurotherapeutics (2007), 4 (1), 97-101CODEN: NEURNV; ISSN:1933-7213. (Elsevier)
A review. The incidence of refractory seizures has remained at 30-40%, even with the approval of nine new anticonvulsants over the past 12 years. In attempts to reduce seizure frequency and severity, physicians routinely resort to combining two or more anticonvulsants, ideally with different mechanisms of action. These combinatorial therapies are difficult to administer for both patient and caregiver and often result in tolerability issues. Hence, a broad spectrum anticonvulsant, with multiple mechanisms of action, that is well tolerated, would provide physicians with an important option in their armamentarium to control seizures. Felbamate initially fit this profile and was demonstrated to effectively control both partial and generalized seizures in clin. studies supporting registration. Unfortunately, unanticipated idiosyncratic toxicity was obsd. after approval and the drug is now relegated to second or third line therapy, depending on patient history and seizure type. Epileptologists still prescribe this drug for refractory seizures, and a recent communication indicates that 35,000 to 46,000 new patients have tried Felbatol (MedPointe Pharmaceuticals, Somerset, NJ) since 1995. The continued utilization of Felbatol, in light of its risk:benefit issues, highlights the need for new efficacious therapeutic options. Fluorofelbamate (Med-Pointe Pharmaceuticals), a phase I drug candidate, was designed to retain the broad spectrum multimechanistic activity of felbamate, with a modified metab. that has demonstrated, in vitro, to avoid the prodn. of the reactive metabolite believed to cause the idiosyncratic toxicity. This drug candidate is one of several carbamates either in development or currently on the market for treatment of seizures and other CNS disorders.
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(b) Bialer, M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin. Invest. Drugs 2006, 15, 637– 647, DOI: 10.1517/13543784.15.6.637
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Xu, S.; Zhu, B.; Teffera, Y.; Pan, D. E.; Caldwell, C. G.; Doss, G.; Stearns, R. A.; Evans, D. C.; Beconi, M. G. Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes. Drug Metab. Dispos. 2005, 33, 121– 130, DOI: 10.1124/dmd.104.001842
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50
Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes
Xu, Shiyao; Zhu, Bing; Teffera, Yohannes; Pan, Deborah E.; Caldwell, Charles G.; Doss, George; Stearns, Ralph A.; Evans, David C.; Beconi, Maria G.
Drug Metabolism and Disposition (2005), 33 (1), 121-130CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)
The current study evaluated the potential for two dipeptidyl peptidase-IV (DPP-IV) inhibitor analogs (1S)-1-(trans-4-{[(4-trifluoromethoxyphenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride and (1S)-1-(trans-4-{[(2,4-difluorophenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride (MRL-A and MRL-B), contg. a fluoropyrrolidine moiety in the structure, to undergo metabolic activation. The irreversible binding of these tritium-labeled compds. to rat liver microsomal protein was time- and NADPH-dependent and was attenuated by the addn. of reduced glutathione (GSH) or N-acetylcysteine (NAC) to the incubation, indicating that chem. reactive intermediates were formed and trapped by these nucleophiles. Mass spectrometric analyses and further trapping expts. with semicarbazide indicated that the fluoropyrrolidine ring had undergone sequential oxidn. and defluorination events resulting in the formation of GSH or NAC conjugates of the pyrrolidine moiety. The bioactivation of MRL-A was catalyzed primarily by rat recombinant CYP3A1 and CYP3A2. Pretreatment of rats with prototypic CYP3A1 and 3A2 inducers (pregnenolone-16α-carbonitrile and dexamethasone) enhanced the extent of bioactivation which, in turn, led to a higher degree of in vitro irreversible binding to microsomal proteins (5- and 9-fold increase, resp.). Herein, the authors describe studies that demonstrate that the fluoropyrrolidine ring is prone to metabolic activation and that GSH or NAC can trap the reactive intermediates to form adducts that provide insight into the mechanisms of bioactivation.
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51
(a) Edmondson, S. D.; Mastracchio, A.; Mathvink, R. J.; He, J.; Harper, B.; Park, Y. J.; Beconi, M.; Di Salvo, J.; Eiermann, G. J.; He, H.; Leiting, B.; Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.; Patel, S. B.; Petrov, A.; Scapin, G.; Shang, J.; Roy, R. S.; Smith, A.; Wu, J.K.; Xu, S.; Zhu, B.; Thornberry, N. A.; Weber, A. E. (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2006, 49, 3614– 3627, DOI: 10.1021/jm060015t
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51a
(2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]- pyridin-6-ylphenyl)butanamide: A selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
Edmondson, Scott D.; Mastracchio, Anthony; Mathvink, Robert J.; He, Jiafang; Harper, Bart; Park, You-Jung; Beconi, Maria; Di Salvo, Jerry; Eiermann, George J.; He, Huaibing; Leiting, Barbara; Leone, Joseph F.; Levorse, Dorothy A.; Lyons, Kathryn; Patel, Reshma A.; Patel, Sangita B.; Petrov, Aleksandr; Scapin, Giovanna; Shang, Jackie; Roy, Ranabir Sinha; Smith, Aaron; Wu, Joseph K.; Xu, Shiyao; Zhu, Bing; Thornberry, Nancy A.; Weber, Ann E.
Journal of Medicinal Chemistry (2006), 49 (12), 3614-3627CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A series of β-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogs led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide I, a potent, orally active DPP-4 inhibitor (IC50 = 6.3 nM) with excellent selectivity, oral bioavailability in preclin. species, and in vivo efficacy in animal models. Compd. I was selected for further characterization as a potential new treatment for type 2 diabetes.
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(b) Sharma, R.; Sun, H.; Piotrowski, D. W.; Ryder, T. F.; Doran, S. D.; Dai, H.; Prakash, C. Metabolism, excretion, and pharmacokinetics of (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone, a dipeptidyl peptidase inhibitor, in rat, dog and human. Drug Metab. Dispos. 2012, 40, 2143– 2161, DOI: 10.1124/dmd.112.047316
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52
Tremblay, M.; Bethell, R. C.; Cordingley, M. G.; Deroy, P.; Duan, J.; Duplessis, M.; Edwards, P. J.; Faucher, A. M.; Halmos, T.; James, C. A.; Kuhn, C.; Lacoste, J. E.; Lamorte, L.; LaPlante, S. R.; Malenfant, É.; Minville, J.; Morency, L.; Morin, S.; Rajotte, D.; Salois, P.; Simoneau, B.; Tremblay, S.; Sturino, C. F. Identification of benzofurano-[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2775– 2780, DOI: 10.1016/j.bmcl.2013.02.042
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(a) Meyer, A.; Imming, P. Benzylisoquinoline alkaloids from the papaveraceae: the heritage of Johannes Gadamer (1867–1928). J. Nat. Prod. 2011, 74, 2482– 2487, DOI: 10.1021/np2005049
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(b) Sriram, D.; Yogeeswari, P.; Thirumurugan, R.; Ratan Bal, T. R. Camptothecin and its analogues: a review on their chemotherapeutic potential. Nat. Prod. Res. 2005, 19, 393– 412, DOI: 10.1080/14786410412331299005
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53b
Camptothecin and its analogues: a review on their chemotherapeutic potential
Sriram, Dharmarajan; Yogeeswari, Perumal; Thirumurugan, Rathinasabapathy; Ratan Bal, Tanushree
Natural Product Research (2005), 19 (4), 393-412CODEN: NPRAAT; ISSN:1478-6419. (Taylor & Francis Ltd.)
A review. Topoisomerase I (Topo-I) is a major target for anticancer drug discovery and design. As a result, Topo-I inhibitors constitute an important class of the current anticancer drugs. To date, all of the Topo-I inhibitors that have been clin. evaluated are analogs of camptothecin (CPT), an ext. of the Chinese tree Camptotheca acuminata. CPT has shown significant antitumor activity to lung, ovarian, breast, pancreas and stomach cancers. In this article the, phytochem. aspect, and various structural modifications are comprehensively reviewed as in rings A, B, C, D and E. Biol. activity of camptothecin, other than anticancer, reported till the year 2003 has also been discussed.
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(c) Olsen, L. R.; Grillo, M. P.; Skonberg, C. Constituents in kava extracts potentially involved in hepatotoxicity: a review. Chem. Res. Toxicol. 2011, 24, 992– 1002, DOI: 10.1021/tx100412m
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53c
Constituents in Kava Extracts Potentially Involved in Hepatotoxicity: A Review
Olsen, Line R.; Grillo, Mark P.; Skonberg, Christian
Chemical Research in Toxicology (2011), 24 (7), 992-1002CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
A review. Aq. kava root prepns. have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava exts. in Western countries, where mainly ethanolic or acetonic exts. are used. The mechanism of toxicity has not been established, although several theories have been put forward. The compn. of the major constituents, the kava lactones, varies according to prepn. method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain compn. of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chem. structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones were identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addn. of GSH to kava exts. has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava ext., such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries.
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54
Murray, M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr. Drug Metab. 2000, 1, 67– 84, DOI: 10.2174/1389200003339270
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Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation
Murray, Michael
Current Drug Metabolism (2000), 1 (1), 67-84CODEN: CDMUBU ISSN:. (Bentham Science Publishers Ltd.)
A review with 110 refs. Cytochrome P 450 (CYP) enzymes catalyze the oxidative conversion of drugs and other lipophilic compds. to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidn. by specific CYPs, whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compds. have been widely employed as com. important pesticide synergists and a no. of derivs. are found in oils and spices. MDP compds. are of considerable toxicol. significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivs. produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clin. importance that possess the MDP structural feature, the synthesis and preclin. evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compds. it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chem. mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clin. value of new drugs.
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(a) Kalgutkar, A. S.; Gardner, I.; Obach, R. S.; Shaffer, C. L.; Callegari, E.; Henne, K. R.; Mutlib, A. E.; Dalvie, D. K.; Lee, J. S.; Nakai, Y.; O’Donnell, J. P.; Boer, J.; Harriman, S. P. A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 2005, 6, 161– 225, DOI: 10.2174/1389200054021799
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55a
A comprehensive listing of bioactivation pathways of organic functional groups
Kalgutkar, Amit S.; Gardner, Iain; Obach, R. Scott; Shaffer, Christopher L.; Callegari, Ernesto; Henne, Kirk R.; Mutlib, Abdul E.; Dalvie, Deepak K.; Lee, Jae S.; Nakai, Yasuhiro; O'Donnell, John P.; Boer, Jason; Harriman, Shawn P.
Current Drug Metabolism (2005), 6 (3), 161-225CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)
A review. The occurrence of idiosyncratic adverse drug reactions during late clin. trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiol. of many drug-induced adverse reactions. Therefore, a thorough examn. of the biochem. reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochem. systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compds. based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as exptl. approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.
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(b) Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol. 2011, 24, 1345– 1410, DOI: 10.1021/tx200168d
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55b
Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States
Stepan, Antonia F.; Walker, Daniel P.; Bauman, Jonathan; Price, David A.; Baillie, Thomas A.; Kalgutkar, Amit S.; Aleo, Michael D.
Chemical Research in Toxicology (2011), 24 (9), 1345-1410CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
A review. Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examd. as part of lead optimization efforts in drug discovery. Likewise, avoidance of "structural alerts" is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards assocd. with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addn., the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a mol. that contains a structural alert (RM pos. or neg.) a cause for concern. Could the mol. in its parent form exert toxicity. Can a low dose drug candidate truly mitigate metab.-dependent and -independent idiosyncratic toxicity risks. In an effort to address these questions, we have retrospectively examd. 68 drugs (recalled or assocd. with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochem. characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our anal. revealed that a significant proportion (∼78-86%) of drugs assocd. with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these mols. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochem. properties such as mol. wt., lipophilicity, etc. Approx. half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chem. architecture, and many were found to be RM-pos. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely assocd. with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addn., competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-pos. drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our anal. suggests a need for a more integrated screening paradigm for chem. hazard identification in drug discovery. Thus, in addn. to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compd.(s)) for lead compds., effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compd. liabilities. However, the prospective use of such data in compd. selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiol. mechanisms assocd. with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the assocd. "body burden" of the parent drug and its metabolites will remain an overarching goal in drug discovery.
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Bolton, J. L.; Trush, M. A.; Penning, T. M.; Dryhurst, G.; Monks, T. J. Role of quinones in toxicology. Chem. Res. Toxicol. 2000, 13, 135– 160, DOI: 10.1021/tx9902082
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56
Role of Quinones in Toxicology
Bolton, Judy L.; Trush, Michael A.; Penning, Trevor M.; Dryhurst, Glenn; Monks, Terrence J.
Chemical Research in Toxicology (2000), 13 (3), 135-160CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
A review and discussion with 298 refs. Quinones represent a class of toxicol. intermediates which can create a variety of hazardous effects in vivo, including acute cytotoxicity, immunotoxicity, and carcinogenesis. The mechanisms by which quinones cause these effects can be quite complex. Quinones are Michael acceptors, and cellular damage can occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active mols. which can redox cycle with their semiquinone radicals, leading to formation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Prodn. of ROS can cause severe oxidative stress within cells through the formation of oxidized cellular macromols., including lipids, proteins, and DNA. Formation of oxidatively damaged bases such as 8-oxodeoxyguanosine has been assocd. with aging and carcinogenesis. Furthermore, ROS can activate a no. of signaling pathways, including protein kinase C and RAS. This review explores the varied cytotoxic effects of quinones using specific examples, including quinones produced from benzene, polycyclic arom. hydrocarbons, estrogens, and catecholamines. The evidence strongly suggests that the numerous mechanisms of quinone toxicity (i.e., alkylation vs. oxidative stress) can be correlated with the known pathol. of the parent compd.(s).
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(a) Hemeryck, A.; De Vriendt, C. A.; Belpaire, F. M. Metoprolol-paroxetine interaction in human liver microsomes: stereoselective aspects and prediction of the in vivo interaction. Drug Metab. Dispos. 2001, 29, 656– 663
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(b) Zhao, S. X.; Dalvie, D. K.; Kelly, J. M.; Soglia, J. R.; Frederick, K. S.; Smith, E. B.; Obach, R. S.; Kalgutkar, A. S. NADPH-dependent covalent binding of [³H]-paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 2007, 20, 1649– 1657, DOI: 10.1021/tx700132x
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(c) Bertelsen, K. M.; Venkatakrishnan, K.; von Moltke, L. L.; Obach, R. S.; Greenblatt, D. J. Apparent mechanism-based inhibition of human CYP 2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 2003, 31, 289– 293, DOI: 10.1124/dmd.31.3.289
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57c
Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: Comparison with fluoxetine and quinidine
Bertelsen, Kirk M.; Venkatakrishnan, Karthik; Von Moltke, Lisa L.; Obach, R. Scott; Greenblatt, David J.
Drug Metabolism and Disposition (2003), 31 (3), 289-293CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)
Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P 450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To det. whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estd. by varying the time of preincubation as well as the concn. of inhibitor. From these data, a Kitz-Wilson plot was constructed, allowing the estn. of both an apparent inactivator concn. required for half-maximal inactivation (KI) and the maximal rate const. of inactivation (KINACT) value for this interaction. Preincubation of paroxetine with human liver microsomes caused an approx. 8-fold redn. in the IC50 value (0.34 vs. 2.54 μM). Time-dependent inhibition was demonstrated with an apparent KI of 4.85 μM and an apparent KINACT value of 0.17 min-1. Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. This pattern is consistent with the metab. of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P 450 enzymes. In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine.
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(a) Anzali, S.; Mederski, W. W. K. R.; Osswald, M.; Dorsch, D. 1. Endothelin antagonists: search for surrogates of methylendioxyphenyl by means of a kohonen neural network. Bioorg. Med. Chem. Lett. 1998, 8, 11– 16, DOI: 10.1016/S0960-894X(97)10150-0
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(b) Iyengar, R. R.; Lynch, J. K.; Mulhern, M. M.; Judd, A. S.; Freeman, J. C.; Gao, J.; Souers, A. J.; Zhao, G.; Wodka, D.; Falls, H. D.; Brodjian, S.; Dayton, B. D.; Reilly, R. M.; Swanson, S.; Su, Z.; Martin, R. L.; Leitz, S. T.; Houseman, K. A.; Diaz, G.; Collins, C. A.; Sham, H. L.; Kym, P. R. An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists. Bioorg. Med. Chem. Lett. 2007, 17, 874– 878, DOI: 10.1016/j.bmcl.2006.11.065
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(c) Bardelle, C.; Barlaam, B.; Brooks, N.; Coleman, T.; Cross, D.; Ducray, R.; Green, I.; Lambert-van der Brempt, C.; Olivier, A.; Read, J. Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 6242– 6245, DOI: 10.1016/j.bmcl.2010.08.100
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(d) Orr, S. T. M.; Ripp, S. L.; Ballard, T. E.; Henderson, J. L.; Scott, D. O.; Obach, R. S.; Sun, H.; Kalgutkar, A. S. Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure–activity relationships and discovery strategies to mitigate drug–drug interaction risks. J. Med. Chem. 2012, 55, 4896– 4933, DOI: 10.1021/jm300065h
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58d
Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure-Activity Relationships and Discovery Strategies To Mitigate Drug-Drug Interaction Risks
Orr, Suvi T. M.; Ripp, Sharon L.; Ballard, T. Eric; Henderson, Jaclyn L.; Scott, Dennis O.; Obach, R. Scott; Sun, Hao; Kalgutkar, Amit S.
Journal of Medicinal Chemistry (2012), 55 (11), 4896-4933CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The importance of mitigating drug-drug interaction (DDI) risks, which arise from inhibition of major human cytochrome P 450 enzymes is a well-established component of the lead optimization process in drug discovery. More recently, there has been much interest in clin. DDIs potentially arising via time- and concn.-dependent cytochrome P 450 inhibition, a phenomenon consistent with mechanism-based inactivation. Inactivated P 450 is catalytically incompetent and must be replenished by newly synthesized protein. Consequently, time-dependent inhibition of P450s presents a greater safety concern compared to reversible inhibition because of the increased propensity for pharmacokinetic interactions upon multiple dosing and the sustained duration of these interactions after discontinuation of the mechanism-based inactivator. Mechanism-based or time-dependent P 450 inhibitors pose an addnl. risk of idiosyncratic drug toxicity since the mechanism of time-dependency often involves the formation of reactive metabolites, which can react with proteins other than the P 450 isoenzyme responsible for catalysis. in vitro time-dependent inhibition (TDI) of P 450 enzymes is now routinely assessed as part of lead optimization efforts in preclin. drug discovery. However, identification of an in vitro TDI liability can raise several questions such as: What is the mechanism of TDI. Does it involve the formation of reactive metabolites. Is there a 1:1 correlation between P 450 TDI and RM formation (as measured from reactive metabolite trapping studies). What is the likelihood that a P 450 time-dependent inhibitor will also cause toxicity. What are the DDI risk mitigation options when dealing with P 450 inactivators in drug discovery - compd. progression or termination. Several drugs exhibit in vitro TDI of P 450 enzymes, but only a fraction thereof causes clin. DDIs. Hence, when do we initiate labor-intensive medicinal chem. efforts to design compds. devoid of P 450 TDI liability. What are the best methods to precisely predict the likelihood of occurrence of clin. DDIs with drug candidates that inactivate P 450 enzymes. What are (if any) the qualifying considerations for clin. progression of a P 450 time-dependent inactivator with projected clin. DDI risks. In an effort to address these questions and hopefully provide answers to some of them, we embarked on the present venture wherein we highlight the current state-of-the-art knowledge in this field with a special emphasis on (a) available biochem. and mechanistic approaches in drug discovery to examine TDI of P 450 isoenzymes with new chem. entities, (b) structure-activity relationship studies with marketed drugs assocd. with DDIs via P 450 inactivation, (c) case studies of medicinal chem. tactics to abrogate P 450 inactivation liability, (d) strategies for progression of P 450 TDI-pos. drug candidates, and (e) the utility of in silico methodol., including the use of physiol.-based pharmacokinetic simulators, in drug discovery to predict the magnitude of clin. DDIs risks anticipated with new clin. candidates.
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(e) Crawford, J. J.; Kenny, P. W.; Bowyer, J.; Cook, C. R.; Finlayson, J. E.; Heyes, C.; Highton, A. J.; Hudson, J. A.; Jestel, A.; Krapp, S.; Martin, S.; MacFaul, P. A.; McDermott, B. P.; McGuire, T. M.; Morley, A. D.; Morris, J. J.; Page, K. M.; Rosenbrier Ribeiro, L.; Sawney, H.; Steinbacher, S.; Smith, C.; Dossetter, A. G. Pharmacokinetic benefits of 3,4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors. J. Med. Chem. 2012, 55, 8827– 8837, DOI: 10.1021/jm301119s
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59
Uttamsingh, V.; Gallegos, R.; Liu, J. F.; Harbeson, S. L.; Bridson, G. W.; Cheng, C.; Wells, D. S.; Graham, P. B.; Zelle, R.; Tung, R. Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine. J. Pharmacol. Exp. Ther. 2015, 354, 43– 54, DOI: 10.1124/jpet.115.223768
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Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine
Uttamsingh, Vinita; Gallegos, Richard; Liu, Julie F.; Harbeson, Scott L.; Bridson, Gary W.; Cheng, Changfu; Wells, David S.; Graham, Philip B.; Zelle, Robert; Tung, Roger
Journal of Pharmacology and Experimental Therapeutics (2015), 354 (1), 43-54CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)
Selective deuterium substitution as a means of ameliorating clin. relevant pharmacokinetic drug interactions is demonstrated in this study. Carbon-deuterium bonds are more stable than corresponding carbon-hydrogen bonds. Using a precision deuteration platform, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium. The new chem. entity, CTP-347 [(3S,4R)-3-((2,2-dideuterobenzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine], demonstrated similar selectivity for the serotonin receptor, as well as similar neurotransmitter uptake inhibition in an in vitro rat synaptosome model, as unmodified paroxetine. However, human liver microsomes cleared CTP-347 faster than paroxetine as a result of decreased inactivation of CYP2D6. In phase 1 studies, CTP-347 wasmetabolized more rapidly in humans and exhibited a lower pharmacokinetic accumulation index than paroxetine. These alterations in the metab. profile resulted in significantly reduced drug-drug interactions between CTP-347 and two other CYP2D6-metabolized drugs: tamoxifen (in vitro) and dextromethorphan (in humans). Our results show that precision deuteration can improve the metab. profiles of existing pharmacotherapies without affecting their intrinsic pharmacologies.
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(a) Vasudevan, A.; Wodka, D.; Verzal, M. K.; Souers, A. J.; Gao, J.; Brodjian, S.; Fry, D.; Dayton, B.; Marsh, K. C.; Hernandez, L. E.; Ogiela, C. A.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2. Bioorg. Med. Chem. Lett. 2004, 14, 4879– 4882, DOI: 10.1016/j.bmcl.2004.07.034
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(b) Nuzzi, A.; Fiasella, A.; Ortega, J. A.; Pagliuca, C.; Ponzano, S.; Pizzirani, D.; Mandrup Bertozzi, S.; Ottonello, G.; Tarozzo, G.; Reggiani, A.; Bandiera, T.; Bertozzi, F.; Piomelli, D. Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies. Eur. J. Med. Chem. 2016, 111, 138– 159, DOI: 10.1016/j.ejmech.2016.01.046
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60b
Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies
Nuzzi, Andrea; Fiasella, Annalisa; Ortega, Jose Antonio; Pagliuca, Chiara; Ponzano, Stefano; Pizzirani, Daniela; Bertozzi, Sine Mandrup; Ottonello, Giuliana; Tarozzo, Glauco; Reggiani, Angelo; Bandiera, Tiziano; Bertozzi, Fabio; Piomelli, Daniele
European Journal of Medicinal Chemistry (2016), 111 (), 138-159CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate I is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, the authors describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivs., which have led to the identification of I, and expand these studies to elucidate the principal structural and stereochem. features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of II, a novel inhibitor of human NAAA that shows an improved physicochem. and drug-like profile relative to I. This favorable profile, along with the structural diversity of the carbamic acid chain of I, identify this compd. as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.
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(a) Guo, Z.; Zhu, Y.-F.; Gross, T. D.; Tucci, F. C.; Gao, Y.; Moorjani, M.; Connors, P. .J., Jr.; Rowbottom, M. W.; Chen, Y.; Struthers, R. S.; Xie, Q.; Saunders, J.; Reinhart, G.; Chen, T. K.; Killam Bonneville, A. L.; Chen, C. Synthesis and Structure-activity relationships of 1-arylmethyl-5-aryl-6-methyluracils as potent gonadotropin-releasing hormone receptor antagonists. J. Med. Chem. 2004, 47, 1259– 1271, DOI: 10.1021/jm030472z
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(b) Lynch, J. K.; Freeman, J. C.; Judd, A. S.; Iyengar, R.; Mulhern, M.; Zhao, G.; Napier, J. J.; Wodka, D.; Brodjian, S.; Dayton, B. D.; Falls, D.; Ogiela, C.; Reilly, R. M.; Campbell, T. J.; Polakowski, J. S.; Hernandez, L.; Marsh, K. C.; Shapiro, R.; Knourek-Segel, V.; Droz, B.; Bush, E.; Brune, M.; Preusser, L. C.; Fryer, R. M.; Reinhart, G. A.; Houseman, K.; Diaz, G.; Mikhail, A.; Limberis, J. T.; Sham, H. L.; Collins, C. A.; Kym, P. R. Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety. J. Med. Chem. 2006, 49, 6569– 6584, DOI: 10.1021/jm060683e
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62
Malamas, M. S.; Erdei, J.; Gunawan, I.; Barnes, K.; Johnson, M.; Hui, Y.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Olland, A.; Bard, J.; Robichaud, A. J. Aminoimidazoles as potent and selective human β-secretase (BACE1) inhibitors. J. Med. Chem. 2009, 52, 6314– 6323, DOI: 10.1021/jm9006752
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63
Rose, W. C.; Marathe, P. H.; Jang, G. R.; Monticello, T. M.; Balasubramanian, B. N.; Long, B.; Fairchild, C. R.; Wall, M. E.; Wani, M. C. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother. Pharmacol. 2006, 58, 73– 85, DOI: 10.1007/s00280-005-0128-y
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63
Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization
Rose, William C.; Marathe, Punit H.; Jang, Graham R.; Monticello, Thomas M.; Balasubramanian, Balu N.; Long, Byron; Fairchild, Craig R.; Wall, Monroe E.; Wani, Mansukh C.
Cancer Chemotherapy and Pharmacology (2006), 58 (1), 73-85CODEN: CCPHDZ; ISSN:0344-5704. (Springer)
Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacol., toxicol., metabolic and pharmacokinetic developmental potential. Methods: In vitro and in vivo assays were used to assess the compds. for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclin. antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicol. assessment of GI injury in mice. The generation of parent compd. from BMS-422461 was qual. similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equil. was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. Conclusions: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclin. GI toxicity, make this novel camptothecin analog attractive for clin. development.
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Trachsel, D.; Hadorn, M.; Baumberger, F. Synthesis of fluoro analogues of 3,4-(methylenedioxy)amphetamine (MDA) and its derivatives. Chem. Biodivers. 2009, 6, 2115– 2135
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65
(a) Van Goor, F.; Hadida, S.; Grootenhuis, P. D. J.; Burton, B.; Stack, J. H.; Straley, K. S.; Decker, C. J.; Miller, M.; McCartney, J.; Olson, E. R.; Wine, J. J.; Frizzell, R. A.; Ashlock, M.; Negulescu, P. A. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 18843– 18848, DOI: 10.1073/pnas.1105787108
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65a
Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A.
Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (46), 18843-18848, S18843/1-S18843/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amts. of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small mols. Here we describe the in vitro pharmacol. of VX-809, a CFTR corrector that was advanced into clin. development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approx. 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level assocd. with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR cor. by VX-809 exhibited biochem. and functional characteristics similar to normal CFTR, including biochem. susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.
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(b) Deeks, E. D. Lumacaftor/ivacaftor: a review in cystic fibrosis. Drugs 2016, 76, 1191– 1201, DOI: 10.1007/s40265-016-0611-2
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65b
Lumacaftor/Ivacaftor: A Review in Cystic Fibrosis
Deeks, Emma D.
Drugs (2016), 76 (12), 1191-1201CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
Lumacaftor/ivacaftor (Orkambi) is a fixed-dose tablet contg. a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride. In two 24-wk trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with std. therapy, was assocd. with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory vol. in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clin. meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI). In an ongoing extension of these studies (PROGRESS), lumacaftor plus ivacaftor provided clin. benefit over a further 72 wk of treatment. Lumacaftor plus ivacaftor had an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature. Thus, lumacaftor/ivacaftor expands the treatment options available for patients with cystic fibrosis homozygous for the F508del-CFTR mutation, although its precise place in clin. practice remains to be detd.
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66
Keith, J. M.; Jones, W. M.; Tichenor, M.; Liu, J.; Seierstad, M.; Palmer, J. A.; Webb, M.; Karbarz, M.; Scott, B. P.; Wilson, S. J.; Luo, L.; Wennerholm, M. L.; Chang, L.; Rizzolio, M.; Rynberg, R.; Chaplan, S. R.; Breitenbucher, J. G. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 2015, 6, 1204– 1208, DOI: 10.1021/acsmedchemlett.5b00353
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66
Preclinical Characterization of the FAAH Inhibitor JNJ-42165279
Keith, John M.; Jones, William M.; Tichenor, Mark; Liu, Jing; Seierstad, Mark; Palmer, James A.; Webb, Michael; Karbarz, Mark; Scott, Brian P.; Wilson, Sandy J.; Luo, Lin; Wennerholm, Michelle L.; Chang, Leon; Rizzolio, Michele; Rynberg, Raymond; Chaplan, Sandra R.; Breitenbucher, J. Guy
ACS Medicinal Chemistry Letters (2015), 6 (12), 1204-1208CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
The preclin. characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 I is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concns. of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compd. was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good phys., ADME, and PD properties of JNJ-42165279 supported it entering the clin. portfolio.
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Buissonneaud, D. Y.; van Mourik, T.; O’Hagan, D. A DFT study on the origin of the fluorine gauche effect in substituted fluoroethanes. Tetrahedron 2010, 66, 2196– 2202, DOI: 10.1016/j.tet.2010.01.049
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67
A DFT study on the origin of the fluorine gauche effect in substituted fluoroethanes
Buissonneaud, David Y.; van Mourik, Tanja; O'Hagan, David
Tetrahedron (2010), 66 (12), 2196-2202CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
DFT derived conformational energy profiles of a series of β-substituted α-fluoroethanes (F-CH2CH2-X) have been explored where the substituent X was varied as NH3+, OCOH, NCO, NO2, NHCHO, F, N3, CH=NH, NCS, CH=C=CH2, CH3, CH=CH2, NC, CN, CHO, and CCH. Comparisons were correlated relative to 1,2-difluoroethane, a compd. which exhibits a well known gauche preference. Only four of the compds. displayed an anti preference, with the large majority preferring a gauche conformation. In particular the influence of steric and electrostatic attraction/repulsion between the fluorine atom and the X-substituent was explored by evaluating rotational energy profiles for all compds. and sep. NBO correlations were evaluated to assess the contribution of hyperconjugation to the minimized gauche and anti conformers. In the event the gauche preference for 1,2-difluoroethane was shown to have an origin due largely to σ(C-H)→σ*(C-F) hyperconjugative interactions, whereas the conformational preference for the remaining structures is rationalized by hyperconjugative as well as steric and electrostatic contributions. The anti preferred compds. 13, 14 and 16 possessed triple bonds and the preference arose due to fluorine/p-orbital repulsion.
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68
(a) Deniau, G.; Slawin, A. M. Z.; Lebl, T.; Chorki, F.; Issberner, J. P.; van Mourik, T.; Heygate, J. M.; Lambert, J. J.; Etherington, L. A.; Sillar, K. T.; O’Hagan, D. Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-γ-aminobutyric acid ((R)- and (S)-3F-GABA): an analogue of the neurotransmitter GABA. ChemBioChem 2007, 8, 2265– 2274, DOI: 10.1002/cbic.200700371
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68a
Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-γ-aminobutyric acid ((R)- and (S)-3F-GABA): an analog of the neurotransmitter GABA
Deniau, Gildas; Slawin, Alexandra M. Z.; Lebl, Tomas; Chorki, Fatima; Issberner, Jon P.; van Mourik, Tanja; Heygate, Judith M.; Lambert, Jeremy J.; Etherington, Lori-An; Sillar, Keith T.; O'Hagan, David
ChemBioChem (2007), 8 (18), 2265-2274CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
β-Aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neurotransmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enantiomers of 3-fluoro-GABA (2, 3F-GABA). DFT calcns. were carried out in a continuum solvent model (PCM-B3LYP) to est. the preferred conformations of 3F-GABA in aq. soln. NMR coupling consts. were calcd. for each conformer and were then used to simulate the NMR spectra to evaluate the soln. conformation of 3F-GABA. A preliminary evaluation of the 3F-GABA enantiomers shows that they act similarly as agonists of cloned GABAA receptors; however, they behave quite differently in a whole animal (Xenopus laevis tadpole model).
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(b) Yamamoto, I.; Deniau, G. P.; Gavande, N.; Chebib, M.; Johnston, G. A. R.; O’Hagan, D. Agonist responses of (R)- and (S)-3-fluoro-γ-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABA_C receptors. Chem. Commun. 2011, 47, 7956– 7958, DOI: 10.1039/c1cc12141c
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(c) Clift, M. D.; Ji, H.; Deniau, G. P.; O’Hagan, D.; Silverman, R. B. Enantiomers of 4-amino-3-fluorobutanoic acid as substrates for γ-aminobutyric acid aminotransferase. Conformational probes for GABA binding. Biochemistry 2007, 46, 13819– 13828, DOI: 10.1021/bi701249q
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68c
Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for γ-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA Binding
Clift, Michael D.; Ji, Haitao; Deniau, Gildas P.; O'Hagan, David; Silverman, Richard B.
Biochemistry (2007), 46 (48), 13819-13828CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
γ-Aminobutyric acid aminotransferase (GABA-AT), a pyridoxal 5'-phosphate dependent enzyme, catalyzes the degrdn. of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) to succinic semialdehyde with concomitant conversion of pyridoxal 5'-phosphate (PLP) to pyridoxamine 5'-phosphate (PMP). The enzyme then catalyzes the conversion of α-ketoglutarate to the excitatory neurotransmitter L-glutamate. Racemic 4-amino-3-fluorobutanoic acid (3-F-GABA) was shown previously to act as a substrate for GABA-AT, not for transamination, but for HF elimination. Here we report studies of the reaction catalyzed by GABA-AT on (R)- and (S)-3-F-GABA. Neither enantiomer is a substrate for transamination. Very little elimination from the (S)-enantiomer was detected using a coupled enzyme assay; The rate of elimination of HF from the (R)-enantiomer is at least 10 times greater than that for the (S)-enantiomer. The (R)-enantiomer is about 20 times more efficient as a substrate for GABA-AT catalyzed HF elimination than GABA is a substrate for transamination. The (R)-enantiomer also inhibits the transamination of GABA 10 times more effectively than the (S)-enantiomer. Using a combination of computer modeling and the knowledge that vicinal C-F and C-NH3+ bonds have a strong preference to align gauche rather than anti to each other, it is concluded that on binding of free 3-F-GABA to GABA-AT the optimal conformation places the C-NH3+ and C-F bonds gauche in the (R)-enantiomer but anti in the (S)-enantiomer. Furthermore, the dynamic binding process and the bioactive conformation of GABA bound to GABA-AT have been inferred on the basis of the different biol. behavior of the two enantiomers of 3-F-GABA when they bind to the enzyme. The present study suggests that the C-F bond can be utilized as a conformational probe to explore the dynamic binding process and provide insight into the bioactive conformation of substrates, which cannot be easily detd. by other biophys. approaches.
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(d) Crittenden, D. L.; Chebib, M.; Jordan, M. J. T. A quantitative structure-activity relationship investigation into agonist binding at GABA_C receptors. J. Mol. Struct.: THEOCHEM 2005, 755, 81– 89, DOI: 10.1016/j.theochem.2005.07.029
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68d
A quantitative structure-activity relationship investigation into agonist binding at GABAC receptors
Crittenden, Deborah L.; Chebib, Mary; Jordan, Meredith J. T.
Journal of Molecular Structure: THEOCHEM (2005), 755 (1-3), 81-89CODEN: THEODJ; ISSN:0166-1280. (Elsevier B.V.)
The quant. structure-activity relationship (QSAR) model constructed in this work represents the first quant. investigation into agonist binding at GABAC receptors. This model is based upon the three-dimensional structures of γ-aminobutyric acid (GABA) and 12 other biol. active GABA analogs. These structures are obtained by geometry optimization and conformational exploration at MP2/6-31 + G* within the conductor-like screening solvation model (COSMO). The biol. activity data are obtained from previous two-electrode voltage clamp electrophysiol. studies on recombinant GABAC ρ1 receptors expressed in Xenopus laevis oocytes. A QSAR model to predict GABAC agonist binding is constructed from mol. superposition data, generated by least-squares superposition of the stable aq. phase conformations of GABA and its known biol. active analogs to the bioactive conformation of TACA, the most potent GABAC receptor agonist. A significant relationship is found between the root-mean-squared deviation in at. position for the stable conformer of each GABA analog most closely fitting the template TACA structure and the natural log of the normalized biol. activity (R2 = 0.91, p < 0.0001), On the basis of mol. superposition and QSAR results, a pharmacophore model describing three-dimensional features and key interactions at the GABAC receptor binding site is proposed. As there exists no direct exptl. knowledge of structure of the GABAC binding site, this approach provides a feasible and reliable alternative to gain insight into its three-dimensional structure.
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69
(a) Hunter, L.; Jolliffe, K. A.; Jordan, M. J. T.; Jensen, P.; MacQuart, R. B. Synthesis and conformational analysis of α,β-difluoro-γ-amino acid derivatives. Chem. - Eur. J. 2011, 17, 2340– 2343, DOI: 10.1002/chem.201003320
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69a
Synthesis and conformational analysis of α,β-difluoro-γ-amino acid derivatives
Hunter, Luke; Jolliffe, Katrina A.; Jordan, Meredith J. T.; Jensen, Paul; MacQuart, Rene B.
Chemistry - A European Journal (2011), 17 (8), 2340-2343, S2340/1-S2340/61CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Synthetic access has been archived to all possible stereoisomers of the α,β-difluoro-γ-amino acid motif. These building blocks can readily be coupled to other amino acids under std. conditions with no detectable epimerization, and the resulting, diastereomeric peptides exhibit different, but predictable, conformational behavior. The α,β-difluoro-γ-amino acid motif described here should be of relevance in the future design of shape-controlled bioactive amino acids and peptides.
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(b) Yamamoto, I.; Jordan, M. J. T.; Gavande, N.; Doddareddy, M. R.; Chebib, M.; Hunter, L. The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABA C receptor. Chem. Commun. 2012, 48, 829– 831, DOI: 10.1039/C1CC15816C
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69b
The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABAC receptor
Yamamoto, Izumi; Jordan, Meredith J. T.; Gavande, Navnath; Doddareddy, Munikumar R.; Chebib, Mary; Hunter, Luke
Chemical Communications (Cambridge, United Kingdom) (2012), 48 (6), 829-831CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
The conformational behavior and GABA receptor activity of the different stereoisomers of 2,3-difluoro-4-aminobutyric acid are described. Two enantiomeric GABAC-active ligands are identified, one of which is an agonist while the other is an antagonist. The results support an existing QSAR model of the bioactive geometry of GABA at GABAC.
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70
Chia, P. W.; Livesey, M. R.; Slawin, A. M. Z.; Van Mourik, T.; Wyllie, D. J. A.; O’Hagan, D. 3-Fluoro-N-methyl-D-aspartic acid (3F-NMDA) stereoisomers as conformational probes for exploring agonist binding at NMDA receptors. Chem. - Eur. J. 2012, 18, 8813– 8819, DOI: 10.1002/chem.201200071
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70
3-Fluoro-N-methyl-L-aspartic acid (3F-NMDA) Stereoisomers as Conformational Probes for Exploring Agonist Binding at NMDA Receptors
Chia, Poh Wai; Livesey, Matthew R.; Slawin, Alexandra M. Z.; Mourik, Tanja van; Wyllie, David J. A.; O'Hagan, David
Chemistry - A European Journal (2012), 18 (28), 8813-8819, S8813/1-S8813/6CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
N-Methyl-L-aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a C-F bond at the 3-position of (S)-NMDA generates either the (2S,3S)- or (2S,3R)- diastereoisomers of 3F-NMDA. The individual diastereoisomers were prepd. by synthesis in enantiomerically pure forms and (2S,3S)-3F-NMDA is an agonist with a comparable potency to NMDA itself, whereas the (2S,3R)-diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the C-F bond (2S,3S)-3F-NMDA to adopt a gauche conformation to the C-N+ bond in the binding conformation, whereas the (2S,3R)-3F-NMDA forces these bonds anti, losing electrostatic stabilization, to achieve the required binding conformation. These observations illustrate the utility of stereoselective fluorination in influencing the mol. conformation of β-fluorinated amino acids and thus probing the active conformations of bioactive compds. at receptors.
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71
Hu, X. G.; Thomas, D. S.; Griffith, R.; Hunter, L. Stereoselective fluorination alters the geometry of a cyclic peptide: exploration of backbone-fluorinated analogues of unguisin A. Angew. Chem., Int. Ed. 2014, 53, 6176– 6179, DOI: 10.1002/anie.201403071
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71
Stereoselective fluorination alters the geometry of a cyclic peptide: Exploration of backbone-fluorinated analogues of Unguisin A
Hu, Xiang-Guo; Thomas, Donald S.; Griffith, Renate; Hunter, Luke
Angewandte Chemie, International Edition (2014), 53 (24), 6176-6179CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
New methods for enhancing the efficiency of peptide cyclization, and for fine-tuning the conformations of cyclic peptides, are valuable from a drug development perspective. Herein stereoselective fluorination is investigated as a new strategy for achieving these goals. Four vicinal difluorinated analogs of the natural cyclic heptapeptide unguisin A have been efficiently synthesized. The analogs are found to adopt dramatically different secondary structures, controlled by the fluorine stereochem.
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72
Hodges, J. A.; Raines, R. T. Stereoelectronic effects on collagen stability: the dichotomy of 4-fluoroproline diastereomers. J. Am. Chem. Soc. 2003, 125, 9262– 9263, DOI: 10.1021/ja035881z
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72
Stereoelectronic Effects on Collagen Stability: The Dichotomy of 4-Fluoroproline Diastereomers
Hodges, Jonathan A.; Raines, Ronald T.
Journal of the American Chemical Society (2003), 125 (31), 9262-9263CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Collagen is the most abundant protein in animals. Natural collagen consists of a triple helix of (Xaa-Yaa-Gly)n chains, in which the Xaa and Yaa residues are often L-proline. Here, a (2S,4S)-4-fluoroproline (flp) residue is shown to be greatly stabilizing in the Xaa position (but destabilizing in the Yaa position). In contrast, a (2S,4R)-4-fluoroproline (Flp) residue is shown to be greatly destabilizing in the Xaa position (but stabilizing in the Yaa position). The dichotomous effect of the diastereomers appears to arise from a gauche effect, which alters pyrrolidine ring pucker and hence properly (or improperly) preorganizes main-chain dihedral angles. Thus, the rational use of stereoelectronic effects can enhance the conformational stability of a protein.
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73
(a) Jakobsche, C. E.; Choudhary, A.; Miller, S. J.; Raines, R. T. n→π* Interaction and n)(π Pauli repulsion are antagonistic for protein stability. J. Am. Chem. Soc. 2010, 132, 6651– 6653, DOI: 10.1021/ja100931y
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73a
n → π* Interaction and n)(π Pauli Repulsion Are Antagonistic for Protein Stability
Jakobsche, Charles E.; Choudhary, Amit; Miller, Scott J.; Raines, Ronald T.
Journal of the American Chemical Society (2010), 132 (19), 6651-6653CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
In many common protein secondary structures, such as α-, 310, and polyproline II helixes, an n → π* interaction places the adjacent backbone amide carbonyl groups in close proximity to each other. This interaction, which is reminiscent of the Burgi-Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (Oi-1) of a peptide bond over the antibonding orbital (π*) of Ci:Oi of the subsequent peptide bond. Such a proximal arrangement of the amide carbonyl groups should be opposed by the Pauli repulsion between the lone pairs (n) of Oi-1 and the bonding orbital (π) of Ci:Oi. We explored the conformational effects of this Pauli repulsion by employing common peptidomimetics, wherein the n → π* interaction is attenuated while the Pauli repulsion is retained. Our results indicate that this Pauli repulsion prevents the attainment of such proximal arrangement of the carbonyl groups in the absence of the n → π* interaction. This finding indicates that the poor mimicry of the amide bond by many peptidomimetics stems from their inability to partake in the n → π* interaction and emphasizes the quantum-mech. nature of the interaction between adjacent amide carbonyl groups in proteins.
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(b) Newberry, R. W.; VanVeller, B.; Guzei, I. A.; Raines, R. T. n→π* Interactions of amides and thioamides: implications for protein stability. J. Am. Chem. Soc. 2013, 135, 7843– 7846, DOI: 10.1021/ja4033583
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73b
n→π* Interactions of Amides and Thioamides: Implications for Protein Stability
Newberry, Robert W.; VanVeller, Brett; Guzei, Ilia A.; Raines, Ronald T.
Journal of the American Chemical Society (2013), 135 (21), 7843-7846CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Carbonyl-carbonyl interactions between adjacent backbone amides have been implicated in the conformational stability of proteins. By combining exptl. and computational approaches, we show that relevant amidic carbonyl groups assoc. through an n→π* donor-acceptor interaction with an energy of at least 0.27 kcal/mol. The n→π* interaction between two thioamides is 3-fold stronger than between two oxoamides due to increased overlap and reduced energy difference between the donor and acceptor orbitals. This result suggests that backbone thioamide incorporation could stabilize protein structures. Finally, we demonstrate that intimate carbonyl interactions are described more completely as donor-acceptor orbital interactions rather than dipole-dipole interactions.
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(c) Kamer, K. J.; Choudhary, A.; Raines, R. T. Intimate interactions with carbonyl groups: dipole-dipole or n→π*?. J. Org. Chem. 2013, 78, 2099– 2103, DOI: 10.1021/jo302265k
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73c
Intimate Interactions with Carbonyl Groups: Dipole-Dipole or n→π*?
Kamer, Kimberli J.; Choudhary, Amit; Raines, Ronald T.
Journal of Organic Chemistry (2013), 78 (5), 2099-2103CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Amide carbonyl groups in proteins can engage in C-O···C=O and C-X···C=O interactions, where X is a halogen. The putative involvement of four poles suggests that these interactions are primarily dipolar. Our survey of crystal structures with a C-X···C=O contact that is short (i.e., within the sum of the X and C van der Waals radii) revealed no preferred C-X···C=O dihedral angle. Moreover, we found that structures with a short X-···C=O contact display the signatures of an n→π* interaction. We conclude that intimate interactions with carbonyl groups do not require a dipole.
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Fukushima, H.; Hiratate, A.; Takahashi, M.; Saito, M.; Munetomo, E.; Kitano, K.; Saito, H.; Takaoka, Y.; Yamamoto, K. Synthesis and structure–activity relationships of potent 3- or 4-substituted-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. 2004, 12, 6053– 6061, DOI: 10.1016/j.bmc.2004.09.010
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75
Jansen, K.; Heirbaut, L.; Verkerk, R.; Cheng, J. D.; Joossens, J.; Cos, P.; Maes, L.; Lambeir, A.-M.; De Meester, I.; Augustyns, K.; Van der Veken, P. Extended structure–activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP). J. Med. Chem. 2014, 57, 3053– 3074, DOI: 10.1021/jm500031w
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75
Extended Structure-Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)
Jansen, Koen; Heirbaut, Leen; Verkerk, Robert; Cheng, Jonathan D.; Joossens, Jurgen; Cos, Paul; Maes, Louis; Lambeir, Anne-Marie; De Meester, Ingrid; Augustyns, Koen; Van der Veken, Pieter
Journal of Medicinal Chemistry (2014), 57 (7), 3053-3074CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncol. applications. The authors previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, the authors explore in detail the structure-activity relationship around this core scaffold. The authors report extensively optimized compds. that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compds. were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.
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76
Staas, D. D.; Savage, K. L.; Sherman, V. L.; Shimp, H. L.; Lyle, T. A.; Tran, L. O.; Wiscount, C. M.; McMasters, D. R.; Sanderson, P. E. J.; Williams, P. D.; Lucas, B. J., Jr.; Krueger, J. A.; Lewis, S. D.; White, R. B.; Yu, S.; Wong, B. K.; Kochansky, C. J.; Anari, M. R.; Yan, Y.; Vacca, J. P. Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability. Bioorg. Med. Chem. 2006, 14, 6900– 6916, DOI: 10.1016/j.bmc.2006.06.040
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76
Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability
Staas, Donnette D.; Savage, Kelly L.; Sherman, Vanessa L.; Shimp, Heidi L.; Lyle, Terry A.; Tran, Lekhanh O.; Wiscount, Catherine M.; McMasters, Daniel R.; Sanderson, Philip E. J.; Williams, Peter D.; Lucas, Bobby J.; Krueger, Julie A.; Lewis, S. Dale; White, Rebecca B.; Yu, Sean; Wong, Bradley K.; Kochansky, Christopher J.; Anari, M. Reza; Yan, Youwei; Vacca, Joseph P.
Bioorganic & Medicinal Chemistry (2006), 14 (20), 6900-6916CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
Previous reports from our labs. described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compds. for further optimization, we identified sites of metab. and designed analogs with 4-fluoroproline in P2 and cyclopropane-contg. side chains in P3 as an approach to reducing metab. and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs contg. (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compds. and by mol. modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compd. from this work, 41 (I), exhibits high potency in a coagulation assay in human plasma (2×APTT = 190 nM), excellent selectivity vs. the digestive enzyme trypsin (Ki = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg).
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77
Chiba, J.; Takayama, G.; Takashi, T.; Yokoyama, M.; Nakayama, A.; Baldwin, J. J.; McDonald, E.; Moriarty, K. J.; Sarko, C. R.; Saionz, K. W.; Swanson, R.; Hussain, Z.; Wong, A.; MachinagA, N. Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists. Bioorg. Med. Chem. 2006, 14, 2725– 2746, DOI: 10.1016/j.bmc.2005.11.058
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78
(a) Wang, Y.; Callejo, R.; Slawin, A. M. Z.; O’Hagan, D. The difluoromethylene (CF₂) group in aliphatic chains: synthesis and conformational preference of palmitic acids and nonadecane containing CF₂ groups. Beilstein J. Org. Chem. 2014, 10, 18– 25, DOI: 10.3762/bjoc.10.4
[Crossref], [PubMed], [CAS], Google Scholar
78a
The difluoromethylene (CF2) group in aliphatic chains: synthesis and conformational preference of palmitic acids and nonadecane containing CF2 groups
Wang, Yi; Callejo, Ricardo; Slawin, Alexandra M. Z.; O'Hagan, David
Beilstein Journal of Organic Chemistry (2014), 10 (), 18-25, 8 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
The syntheses of palmitic acids and a nonadecane are reported with CF2 groups located 1,3 or 1,4 to each other along the aliph. chain. Specifically 8,8,10,10- and 8,8,11,11-tetrafluorohexadecanoic acids are prepd. as well as the singly modified analog 8,8-difluorohexadecanoic acid. Also 8,8,11,11-tetrafluorononadecane is prepd. as a pure hydrocarbon contg. a 1,4-di-CF2 motif. The modified palmitic acids are characterized by differential scanning calorimetry (DSC) to det. m.ps. and phase behavior relative to palmitic acid (62.5 °C). It emerges that 8,8,11,11-tetrafluorohexadecanoic acid, with the CF2 groups placed 1,4- to each other, has a significantly higher m.p. (89.9 °C) when compared to the other analogs and palmitic acid itself. It is a cryst. compd. and the structure reveals an extended anti-zig-zag chain. Similarly 8,8,11,11-tetrafluorononadecane adopts an extended anti-zig-zag structure. This is rationalized by dipolar relaxation between the two CF2 groups placed 1,4 to each other in the extended anti-zig-zag chain and suggests a design modification for long chain aliphatics which can introduce conformational stability.
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(b) Tavasli, M.; O’Hagan, D.; Pearson, C.; Petty, M. C. The fluorine gauche effect. Langmuir isotherms report the relative conformational stability of (±)-erythro- and (±)-threo-9,10-difluorostearic acids. Chem. Commun. 2002, 1226– 1227, DOI: 10.1039/b202891c
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78b
The fluorine gauche effect. Langmuir isotherms report the relative conformational stability of (±)-erythro- and (±)-threo-9,10-difluorostearic acids
Tavasli, Mustafa; O'Hagan, David; Pearson, Christopher; Petty, Michael C.
Chemical Communications (Cambridge, United Kingdom) (2002), (11), 1226-1227CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
(±)-Erythro- and (±)-threo- 9,10-difluorostearic acids, which differ only by a stereogenic interconversion of a single C-F bond, have significantly different conformational stabilities.
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79
(a) O’Hagan, D. Organofluorine chemistry: synthesis and conformation of vicinal fluoromethylene motifs. J. Org. Chem. 2012, 77, 3689– 3699, DOI: 10.1021/jo300044q
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79a
Organofluorine Chemistry: Synthesis and Conformation of Vicinal Fluoromethylene Motifs
O'Hagan, David
Journal of Organic Chemistry (2012), 77 (8), 3689-3699CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A review. The C-F bond is the most polar bond in org. chem., and thus the bond has a relatively large dipole moment with a significant -ve charge d. on the fluorine atom and correspondingly a +ve charge d. on carbon. The electrostatic nature of the bond renders it the strongest one in org. chem. However, the fluorine atom itself is nonpolarizable, and thus, despite the charge localization on fluorine, it is a poor hydrogen-bonding acceptor. These properties of the C-F bond make it attractive in the design of nonviscous but polar org. compds., with a polarity limited to influencing the intramol. nature of the mol. and less so intermol. interactions with the immediate environment. In this perspective, the synthesis of aliph. chains carrying multivicinal fluoromethylene motifs is described. It emerges that the dipoles of adjacent C-F bonds orientate relative to each other, and thus, individual diastereoisomers display different backbone carbon chain conformations. These conformational preferences recognize the influence of the well-known gauche effect assocd. with 1,2-difluoroethane but extend to considering 1,3-fluorine-fluorine dipolar repulsions. The synthesis of carbon chains carrying two, three, four, five, and six vicinal fluoromethylene motifs is described, with an emphasis on the research done by the authors. These motifs obey almost predictable conformational behavior, and they emerge as candidates for inclusion in the design of performance org. mols.
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(b) Wu, D.; Tian, A.; Sun, H. Conformational properties of 1,3-difluoropropane. J. Phys. Chem. A 1998, 102, 9901– 9905, DOI: 10.1021/jp982164w
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79b
Conformational properties of 1,3-difluoropropane
Wu, D.; Tian, A.; Sun, H.
Journal of Physical Chemistry A (1998), 102 (48), 9901-9905CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
The conformational energy order of F(CH2)3F (I) is identified as GG < AG < AA < GG' at various ab initio calcn. levels. This result is analyzed on the basis of the mol. structures, partial charge distributions, and a mol.-mechanics calcn. A strong dipole-dipole interaction between the highly polarized C-F bonds is the decisive factor detg. the conformational-energy preference between 2 gauche-gauche conformers (GG and GG'). This observation suggests that, in addn. to the gauche effect, the intramol. electrostatic interaction should be considered for studying conformational behaviors of mols. with highly polarized bonds in general. The conformational energies obtained in this work challenge earlier interpretations of exptl. data for I.
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(c) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and structure of stereoisomeric multivicinal hexafluoroalkanes. Angew. Chem., Int. Ed. 2009, 48, 5457– 5460, DOI: 10.1002/anie.200901956
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79c
Synthesis and Structure of Stereoisomeric Multivicinal Hexafluoroalkanes
Hunter, Luke; Kirsch, Peer; Slawin, Alexandra M. Z.; O'Hagan, David
Angewandte Chemie, International Edition (2009), 48 (30), 5457-5460, S5457/1-S5457/63CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The syntheses of hexafluoroalkanes 1a (I) and 1b (II), and tetrafluoroalkane 2 (III) are described. The conformational behavior of 1a (helix), 1b (zigzag), and 2 (zigzag) is consistent with two stereochem. preferences: parallel 1,3-C-F bonds are avoided, and gauche 1,2-C-F bonds are favored.
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80
Scheidt, F.; Selter, P.; Santschi, N.; Holland, M. C.; Dudenko, D. V.; Daniliuc, C.; Mück-Lichtenfeld, C.; Hansen, M. R.; Gilmour, R. Emulating natural product conformation by cooperative, non-covalent fluorine interactions. Chem. - Eur. J. 2017, 23, 6142– 6149, DOI: 10.1002/chem.201604632
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80
Emulating Natural Product Conformation by Cooperative, Non-Covalent Fluorine Interactions
Scheidt, Felix; Selter, Philipp; Santschi, Nico; Holland, Mareike C.; Dudenko, Dmytro V.; Daniliuc, Constantin; Mueck-Lichtenfeld, Christian; Hansen, Michael Ryan; Gilmour, Ryan
Chemistry - A European Journal (2017), 23 (25), 6142-6149CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Pervasive in Nature, the propane unit is an essential component of numerous bioactive mols. These range from acyclic systems, such as the neurotransmitter γ-aminobutyric acid, through to the bicyclic nuclei of various chromanes and dihydrobenzofurans. In the latter case, cyclization via cyclic ether formation ensures a highly pre-organized structure, while linear scaffolds display more dynamic conformational behavior resulting from rotation about the two internal C(sp3)-C(sp3) bonds. In this study, the replacement of -[CH2]- units by -[CHF]- centers is evaluated as a strategy to achieve acyclic conformational control by hindering these internal rotations. Reinforcing, non-covalent fluorine interactions are validated as powerful design features that result in programmable conformational behaviors: These are encoded by the relative configuration of each center. By exploiting cooperative neighboring stereoelectronic effects in a multi-vicinal fluoroalkane it is possible to emulate the overall conformation of the dihydrobenzofuran scaffold found in a variety of natural products with an acyclic mimic. This is described as a function of two bond vectors at the chain termini and validated by combined theor., crystallog. and spectroscopic analyses. In view of the favorable physicochem. properties assocd. with fluorine introduction, this approach to bioactive scaffold design may prove to be expansive.
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81
Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455
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81
Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery
Huchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, Klaus
Journal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences.
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82
Yokokawa, F.; Wang, G.; Chan, W. L.; Ang, S. H.; Wong, J.; Ma, I.; Rao, S. P. S.; Manjunatha, U.; Lakshminarayana, S. B.; Herve, M.; Kounde, C.; Tan, B. H.; Thayalan, P.; Ng, S. H.; Nanjundappa, M.; Ravindran, S.; Gee, P.; Tan, M.; Wei, L.; Goh, A.; Chen, P.-Y.; Lee, K. S.; Zhong, C.; Wagner, T.; Dix, I.; Chatterjee, A. K.; Pethe, K.; Kuhen, K.; Glynne, R.; Smith, P.; Bifani, P.; Jiricek, J. Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents. ACS Med. Chem. Lett. 2013, 4, 451– 455, DOI: 10.1021/ml400071a
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82
Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents
Yokokawa, Fumiaki; Wang, Gang; Chan, Wai Ling; Ang, Shi Hua; Wong, Josephine; Ma, Ida; Rao, Srinivasa P. S.; Manjunatha, Ujjini; Lakshminarayana, Suresh B.; Herve, Maxime; Kounde, Cyrille; Tan, Bee Huat; Thayalan, Pamela; Dick, Thomas; Ng, Seow Hwee; Nanjundappa, Mahesh; Ravindran, Sindhu; Gee, Peck; Tan, Maria; Wei, Liu; Goh, Anne; Chen, Pei-Yu; Lee, Kok Sin; Zhong, Chen; Wagner, Trixie; Dix, Ina; Chatterjee, Arnab K.; Pethe, Kevin; Kuhen, Kelli; Glynne, Richard; Smith, Paul; Bifani, Pablo; Jiricek, Jan
ACS Medicinal Chemistry Letters (2013), 4 (5), 451-455CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
Nonracemic (aryl)(fluoroalkyl)tetrahydropyrazolo[1,5-a]pyrimidinecarboxamides I [R = 4-MeC6H4, 5-Me-2-pyridinyl, 5-methyl-2-furyl, 4-(4-morpholinyl)C6H4, 4-(MeOCH2CH2O)C6H4, 4-(3-oxetanyloxy)C6H4; R1 = F3C, F2HC; R2 = 4-FC6H4CH2, 6-MeO-3-pyridinylmethyl, 5-F-2-pyridinylmethyl] were prepd. stereoselectively as potential antitubercular agents; their inhibition of Mycobacterium tuberculosis (Mtb), their aq. solubilities, their plasma protein binding, and their lipophilicities were detd. I were prepd. from aryl Me ketones, Et trifluoro- or difluoroacetate, and Et 3-amino-4-pyrazolecarboxylate; resoln. of the intermediate cis-aryl(fluoroalkyl)tetrahydropyrazolopyrimidinecarboxylic acids by supercrit. fluid chromatog. followed by amidation or aryl modifications yielded the desired products. While I inhibited Mtb with MIC of 0.13-52.2 μM, ent-I did not inhibit Mtb (MIC > 20 μM). In particular, I (R = 4-MeC6H4; R1 = F3C; R2 = 4-FC6H4CH2) showed a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse antitubercular efficacy model, achieving a redn. of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. I (R = 4-MeC6H4; R1 = F3C; R2 = 4-FC6H4CH2) is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB. The structure of a nonracemic (methylpyridinyl)(trifluoromethyl)tetrahydropyrazolopyrimidinecarboxylic acid intermediate and its abs. configuration were detd. by X-ray crystallog.
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83
Koerts, J.; Soffers, A. E. M. F.; Vervoort, J.; De Jager, A.; Rietjens, I. M. C. M. Occurrence of the NIH shift upon the cytochrome P450-catalyzed in vivo and in vitro aromatic ring hydroxylation of fluorobenzenes. Chem. Res. Toxicol. 1998, 11, 503– 512, DOI: 10.1021/tx980053i
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83
Occurrence of the NIH Shift upon the Cytochrome P450-Catalyzed in Vivo and in Vitro Aromatic Ring Hydroxylation of Fluorobenzenes
Koerts, Janneke; Soffers, Ans E. M. F.; Vervoort, Jacques; De Jager, Adrie; Rietjens, Ivonne M. C. M.
Chemical Research in Toxicology (1998), 11 (5), 503-512CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
The in vivo cytochrome P 450-catalyzed arom. hydroxylation of a series of fluorobenzenes was investigated with special emphasis on the importance of the fluorine NIH shift. The results obtained demonstrate a minor role for the NIH shift in the metab. of the fluorobenzenes to phenolic metabolites in control male Wistar rats. These in vivo results could indicate that (1) the NIH shift is an inherently minor process for fluorine substituents or (2) it is a potentially significant process but the presumed epoxide that leads to formation of the NIH-shifted metabolite is lost to an alternative metabolic pathway. In contrast to the in vivo data, in vitro expts. showed a significant amt. of NIH-shifted metabolites for 1,4-difluorobenzene. This result eliminates the explanation that the NIH shift is an inherently minor process for fluorine substituents. Results of addnl. expts. presented in this paper show that the reduced tendency of fluorine-substituted benzenes to undergo an NIH shift in vivo can-at least in part-be ascribed to the possible existence of alternative pathways for metab. of the epoxide, such as, for example, GSH conjugation, being more efficient for fluorinated than chlorinated benzenes.
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84
(a) Shih, I.-h.; Vliegen, I.; Peng, B.; Yang, H.; Hebner, C.; Paeshuyse, J.; Purstinger, G.; Fenaux, M.; Tian, Y.; Mabery, E.; Qi, X.; Bahador, G.; Paulson, M.; Lehman, L. S.; Bondy, S.; Tse, W.; Reiser, H.; Lee, W. A.; Schmitz, U.; Neyts, J.; Zhong, W. Mechanistic characterization of GS-9190 (tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase. Antimicrob. Agents Chemother. 2011, 55, 4196– 4203, DOI: 10.1128/AAC.00307-11
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(b) Hebner, C. M.; Han, B.; Brendza, K. M.; Nash, M.; Sulfab, M.; Tian, Y.; Hung, M.; Fung, W.; Vivian, R. W.; Trenkle, J.; Taylor, J.; Bjornson, K.; Bondy, S.; Liu, X.; Link, J.; Neyts, J.; Sakowicz, R.; Zhong, W.; Tang, H.; Schmitz, U. The HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function. PLoS One 2012, 7, e39163, DOI: 10.1371/journal.pone.0039163
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84b
The HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function
Hebner, Christy M.; Han, Bin; Brendza, Katherine M.; Nash, Michelle; Sulfab, Maisoun; Tian, Yang; Hung, Magdeleine; Fung, Wanchi; Vivian, Randall W.; Trenkle, James; Taylor, James; Bjornson, Kyla; Bondy, Steven; Liu, Xiaohong; Link, John; Neyts, Johan; Sakowicz, Roman; Zhong, Weidong; Tang, Hengli; Schmitz, Uli
PLoS One (2012), 7 (6), e39163CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
Tegobuvir (TGV) is a novel non-nucleoside inhibitor (NNI) of HCV RNA replication with demonstrated antiviral activity in patients with genotype 1 chronic HCV infection. The mechanism of action of TGV has not been clearly defined despite the identification of resistance mutations mapping to the NS5B polymerase region. TGV does not inhibit NS5B enzymic activity in biochem. assays in vitro, suggesting a more complex antiviral mechanism with cellular components. Here, we demonstrate that TGV exerts anti-HCV activity utilizing a unique chem. activation and subsequent direct interaction with the NS5B protein. Treatment of HCV subgenomic replicon cells with TGV results in a modified form of NS5B with a distinctly altered mobility on a SDS-PAGE gel. Further anal. reveals that the aberrantly migrating NS5B species contains the inhibitor mol. Formation of this complex does not require the presence of any other HCV proteins. The intensity of the aberrantly migrating NS5B species is strongly dependent on cellular glutathione levels as well as CYP 1A activity. Furthermore anal. of NS5B protein purified from a heterologous expression system treated with TGV by mass spectrometry suggests that TGV undergoes a CYP-mediated intracellular activation step and the resulting metabolite, after forming a glutathione conjugate, directly and specifically interacts with NS5B. Taken together, these data demonstrate that upon metabolic activation TGV is a specific, covalent inhibitor of the HCV NS5B polymerase and is mechanistically distinct from other classes of the non-nucleoside inhibitors (NNI) of the viral polymerase.
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(c) Leivers, M.; Miller, J. F.; Chan, S. A.; Lauchli, R.; Liehr, S.; Mo, W.; Ton, T.; Turner, E. M.; Youngman, M.; Falls, J. G.; Long, S.; Mathis, A.; Walker, J. Imidazopyridazine hepatitis C virus polymerase inhibitors. Structure-activity relationship studies and the discovery of a novel, traceless prodrug mechanism. J. Med. Chem. 2014, 57, 1964– 1975, DOI: 10.1021/jm401337x
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(d) Powers, J. P.; Piper, D. E.; Li, Y.; Mayorga, V.; Anzola, J.; Chen, J. M.; Jaen, J. C.; Lee, G.; Liu, J.; Peterson, M. G.; Tonn, G. R.; Ye, Q.; Walker, N. P. C.; Wang, Z. SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase. J. Med. Chem. 2006, 49, 1034– 1046, DOI: 10.1021/jm050859x
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84d
SAR and Mode of Action of Novel Non-Nucleoside Inhibitors of Hepatitis C NS5b RNA Polymerase
Powers, Jay P.; Piper, Derek E.; Li, Yang; Mayorga, Veronica; Anzola, John; Chen, James M.; Jaen, Juan C.; Lee, Gary; Liu, Jinqian; Peterson, M. Greg; Tonn, George R.; Ye, Qiuping; Walker, Nigel P. C.; Wang, Zhulun
Journal of Medicinal Chemistry (2006), 49 (3), 1034-1046CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochem. potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were detd. by x-ray crystallog., and the inhibitors were found to bind in an allosteric binding site sep. from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compds. in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
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85
Pinto, D. J.P.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.; Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. Discovery of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem. 2001, 44, 566– 578, DOI: 10.1021/jm000409z
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86
Alex, A.; Millan, D. S.; Perez, M.; Wakenhut, F.; Whitlock, G. A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. MedChemComm 2011, 2, 669– 674, DOI: 10.1039/c1md00093d
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86
Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space
Alex, Alexander; Millan, David S.; Perez, Manuel; Wakenhut, Florian; Whitlock, Gavin A.
MedChemComm (2011), 2 (7), 669-674CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
Utilizing 'beyond rule of five' chem. space is becoming increasingly important in drug design, but is usually at odds with good oral absorption. The formation of intramol. hydrogen bonds in drug mols. is hypothesised to shield polarity facilitating improved membrane permeability and intestinal absorption. NMR based evidence for intramol. hydrogen bonding in several 'beyond rule of five' oral drugs is described. Furthermore, the propensity for these drugs to form intramol. hydrogen bonds could be predicted for through modeling the lowest energy conformation in the gas phase. The modulation of apparent lipophilicity through intramol. hydrogen bonding in these mols. is supported by intrinsic cell permeability and intestinal absorption data in rat and human.
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87
(a) Hitchcock, S. A. Structural modifications that alter the P-glycoprotein efflux properties of compounds. J. Med. Chem. 2012, 55, 4877– 4895, DOI: 10.1021/jm201136z
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87a
Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds
Hitchcock, Stephen A.
Journal of Medicinal Chemistry (2012), 55 (11), 4877-4895CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
This perspective is focused on structural modifications and strategies that can be applied during compd. optimization in order to modulate the P-glycoprotein efflux properties of small mols. with a particular emphasis on implications for CNS penetration. The precise mol. interactions that confer P-glycoprotein efflux remain relatively poorly defined. The promiscuous nature of P-glycoprotein efflux renders the rational circumvention of efflux, while simultaneously optimizing compds. for eficacy, safety, and pharmacokinetic properties, an extremely challenging undertaking.
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(b) Desai, P. V.; Raub, T. J.; Blanco, M. J. How hydrogen bonds impact P-glycoprotein transport and permeability. Bioorg. Med. Chem. Lett. 2012, 22, 6540– 6548, DOI: 10.1016/j.bmcl.2012.08.059
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87b
How hydrogen bonds impact P-glycoprotein transport and permeability
Desai, Prashant V.; Raub, Thomas J.; Blanco, Maria-Jesus
Bioorganic & Medicinal Chemistry Letters (2012), 22 (21), 6540-6548CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
A review. The requirement to cross a biol. membrane can be a complex process esp. if multidrug transporters such as P-gp must be considered. Drug partitioning into the lipid membrane and efflux by P-gp are tightly coupled processes wherein H-bonding interactions play a key role. All H-bond donors and acceptors are not equal in terms of the strength of the H-bonds that they form, hence it is important to consider their relative strength. Using various examples from literature, we illustrate the benefits of considering the relative strengths of individual H-bonds and introducing intramol. H-bonds to increase membrane permeability and/or decrease P-gp efflux.
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88
(a) Dalvit, C.; Vulpetti, A. Intermolecular and intramolecular hydrogen bonds involving fluorine atoms: implications for recognition, selectivity, and chemical properties. ChemMedChem 2012, 7, 262– 272, DOI: 10.1002/cmdc.201100483
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88a
Intermolecular and Intramolecular Hydrogen Bonds Involving Fluorine Atoms: Implications for Recognition, Selectivity, and Chemical Properties
Dalvit, Claudio; Vulpetti, Anna
ChemMedChem (2012), 7 (2), 262-272CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
A correlation between 19F NMR isotropic chem. shift and close intermol. F···H-X contacts (with X = N or O) has been identified upon anal. of the X-ray crystal structures of fluorinated mols. listed in the Cambridge Structural Database (CSD). An optimal F···X distance involving primary and shielded secondary fluorine atoms in hydrogen-bond formation along with a correlation between F···H distance and F···H-X angle were also derived from the anal. The hydrogen bonds involving fluorine are relevant, not only for the recognition mechanism and stabilization of a preferred conformation, but also for improvement in the permeability of the mols., as shown with examples taken from a proprietary database. Results of an anal. of the small no. of fluorine-contg. natural products listed in the Protein Data Bank (PDB) appear to strengthen the derived correlation between 19F NMR isotropic chem. shift and interactions involving fluorine (also known as the "rule of shielding") and provides a hypothesis for the recognition mechanism and catalytic activity of specific enzymes. Novel chem. scaffolds, based on the rule of shielding, have been designed for recognizing distinct structural motifs present in proteins. It is envisaged that this approach could find useful applications in drug design for the efficient optimization of chem. fragments or promising compds. by increasing potency and selectivity against the desired biomol. target.
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(b) Dalvit, C.; Invernizzi, C.; Vulpetti, A. Fluorine as a hydrogen-bond acceptor: experimental evidence and computational calculations. Chem. - Eur. J. 2014, 20, 11058– 11068, DOI: 10.1002/chem.201402858
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88b
Fluorine as a Hydrogen-Bond Acceptor: Experimental Evidence and Computational Calculations
Dalvit, Claudio; Invernizzi, Christian; Vulpetti, Anna
Chemistry - A European Journal (2014), 20 (35), 11058-11068CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Hydrogen-bonding interactions play an important role in many chem. and biol. systems. Fluorine acting as a hydrogen-bond acceptor in intermol. and intramol. interactions was the subject of many controversial discussions and there are different opinions about it. Recently, the authors proposed a correlation between the propensity of fluorine to be involved in hydrogen bonds and its 19F NMR chem. shift. The authors now provide addnl. exptl. and computational evidence for this correlation. The strength of hydrogen-bond complexes involving the fluorine moieties CH2F, CHF2, and CF3 was measured and characterized in simple systems by using established and novel NMR methods and compared to the known hydrogen-bond complex formed between acetophenone and p-fluorophenol. Implications of these results for 19F NMR screening are analyzed. Computed values of the mol. electrostatic potential at the different fluorine atoms and the anal. of the electron d. topol. at bond crit. points correlate well with the NMR results.
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89
Weiss, M. M.; Williamson, T.; Babu-Khan, S.; Bartberger, M. D.; Brown, J.; Chen, K.; Cheng, Y.; Citron, M.; Croghan, M. D.; Dineen, T. A.; Esmay, J.; Graceffa, R. F.; Harried, S. S.; Hickman, D.; Hitchcock, S. A.; Horne, D. B.; Huang, H.; Imbeah-Ampiah, R.; Judd, T.; Kaller, M. R.; Kreiman, C. R.; La, D. S.; Li, V.; Lopez, P.; Louie, S.; Monenschein, H.; Nguyen, T. T.; Pennington, L. D.; Rattan, C.; San Miguel, T.; Sickmier, E. A.; Wahl, R. C.; Wen, P. H.; Wood, S.; Xue, Q.; Yang, B. H.; Patel, V. F.; Zhong, W. Design and preparation of a potent series of hydroxyethylamine containing β-secretase inhibitors that demonstrate robust reduction of central β-amyloid. J. Med. Chem. 2012, 55, 9009– 9024, DOI: 10.1021/jm300119p
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90
Swahn, B.-M.; Kolmodin, K.; Karlström, S.; von Berg, S.; Söderman, P.; Holenz, J.; Berg, S.; Lindström, J.; Sundström, M.; Turek, D.; Kihlström, J.; Slivo, C.; Andersson, L.; Pyring, D.; Rotticci, D.; Öhberg, L.; Kers, A.; Bogar, K.; von Kieseritzky, F.; Bergh, M.; Olsson, L.-L.; Janson, J.; Eketjäll, S.; Georgievska, B.; Jeppsson, F.; Fälting, J. Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides. J. Med. Chem. 2012, 55, 9346– 9361, DOI: 10.1021/jm3009025
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90
Design and Synthesis of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of β-Amyloid Peptides
Swahn, Britt-Marie; Kolmodin, Karin; Karlstroem, Sofia; von Berg, Stefan; Soederman, Peter; Holenz, Joerg; Berg, Stefan; Lindstroem, Johan; Sundstroem, Marie; Turek, Dominika; Kihlstroem, Jacob; Slivo, Can; Andersson, Lars; Pyring, David; Rotticci, Didier; Oehberg, Liselotte; Kers, Annika; Bogar, Krisztian; Bergh, Margareta; Olsson, Lise-Lotte; Janson, Juliette; Eketjaell, Susanna; Georgievska, Biljana; Jeppsson, Fredrik; Faelting, Johanna
Journal of Medicinal Chemistry (2012), 55 (21), 9346-9361CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clin. candidate drug for Alzheimer's disease, (S)-32 (I, AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain redn. of Aβ40, is discussed. Due to the basic nature of these compds., they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 (II) and (R)-41 (III) showing large in vitro margins with BACE1 cell IC50 values of 8.6 and 0.16 nM, resp., and hERG IC50 values of 16 and 2.8 μM, resp. Several compds. were advanced into pharmacodynamic studies and demonstrated significant redn. of β-amyloid peptides in mouse brain following oral dosing.
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91
Bell, I. M.; Bednar, R. A.; Fay, J. F.; Gallicchio, S. N.; Hochman, J. H.; McMasters, D. R.; Miller-Stein, C.; Moore, E. L.; Mosser, S. D.; Pudvah, N. T.; Quigley, A. G.; Salvatore, C. A.; Stump, C. A.; Theberge, C. R.; Wong, B. K.; Zartman, C. B.; Zhang, X. F.; Kane, S. A.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 6165– 6169, DOI: 10.1016/j.bmcl.2006.09.045
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91
Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists
Bell, Ian M.; Bednar, Rodney A.; Fay, John F.; Gallicchio, Steven N.; Hochman, Jerome H.; McMasters, Daniel R.; Miller-Stein, Cynthia; Moore, Eric L.; Mosser, Scott D.; Pudvah, Nicole T.; Quigley, Amy G.; Salvatore, Christopher A.; Stump, Craig A.; Theberge, Cory R.; Wong, Bradley K.; Zartman, C. Blair; Zhang, Xu-Fang; Kane, Stefanie A.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.
Bioorganic & Medicinal Chemistry Letters (2006), 16 (24), 6165-6169CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
A rapid analog approach to identification of spirohydantoin-based CGRP antagonists provided novel, low mol. wt. leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compd. 12 (I), a potent CGRP receptor antagonist (Ki = 21 nM) with good oral bioavailability in three species.
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92
Koshizawa, T.; Morimoto, T.; Watanabe, G.; Watanabe, T.; Yamasaki, N.; Sawada, Y.; Fukuda, T.; Okuda, A.; Shibuya, K.; Ohgiya, T. Optimization of a novel series of potent and orally bioavailable GPR119 agonists. Bioorg. Med. Chem. Lett. 2017, 27, 3249– 3253, DOI: 10.1016/j.bmcl.2017.06.034
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92
Optimization of a novel series of potent and orally bioavailable GPR119 agonists
Koshizawa, Tomoaki; Morimoto, Toshiharu; Watanabe, Gen; Watanabe, Toshiaki; Yamasaki, Nao; Sawada, Yoshikazu; Fukuda, Tomoaki; Okuda, Ayumu; Shibuya, Kimiyuki; Ohgiya, Tadaaki
Bioorganic & Medicinal Chemistry Letters (2017), 27 (15), 3249-3253CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50 = 129 nM) was improved by replacing the intramol. hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compd. 12 (EC50 = 53 nM). Optimized compd. 26, which was identified by the further optimization of 12, exhibited potent activity (EC50 = 42 nM) with improved clearance in liver microsomes and induced a 33% redn. in blood glucose area under the curve at a dose of 10 mg/kg in an oral glucose tolerance test in C57BL/6N mice.
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93
Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D. A.; Davis, C. D.; Denton, R.; Han, X.; Macci, R.; Mathias, N. R.; Moench, P.; Pin, S. S.; Ren, S. X.; Schartman, R.; Signor, L. J.; Thalody, G.; Widmann, K. A.; Xu, C.; Macor, J. E.; Dubowchik, G. M. Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure. J. Med. Chem. 2008, 51, 4858– 4861, DOI: 10.1021/jm800546t
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93
Discovery of (R)-4-(8-Fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): A Potent Antagonist of the Human Calcitonin Gene-Related Peptide Receptor for Migraine with Rapid and Efficient Intranasal Exposure
Degnan, Andrew P.; Chaturvedula, Prasad V.; Conway, Charles M.; Cook, Deborah A.; Davis, Carl D.; Denton, Rex; Han, Xiaojun; Macci, Robert; Mathias, Neil R.; Moench, Paul; Pin, Sokhom S.; Ren, Shelly X.; Schartman, Richard; Signor, Laura J.; Thalody, George; Widmann, Kimberly A.; Xu, Cen; Macor, John E.; Dubowchik, Gene M.
Journal of Medicinal Chemistry (2008), 51 (16), 4858-4861CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chem. leads suffered from modest potency, significant CYP3A4 inhibition, and poor aq. soly. Herein, we describe the optimization of these leads to give 4 (BMS-694153), a mol. with outstanding potency, a favorable predictive toxicol. profile, and remarkable aq. soly. Compd. 4 has good intranasal bioavailablity in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models.
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Razgulin, A. V.; Mecozzi, S. Binding properties of aromatic carbon-bound fluorine. J. Med. Chem. 2006, 49, 7902– 7906, DOI: 10.1021/jm0600702
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95
(a) Lewis, R. T.; Blackaby, W. P.; Blackburn, T.; Jennings, A. S. R.; Pike, A.; Wilson, R. A.; Hallett, D. J.; Cook, S. M.; Ferris, P.; Marshall, G. R.; Reynolds, D. S.; Sheppard, W. F. A.; Smith, A. J.; Sohal, B.; Stanley, J.; Tye, S. J.; Wafford, K. A.; Atack, J. R. A pyridazine series of α2/α3 subtype selective GABA_A agonists for the treatment of anxiety. J. Med. Chem. 2006, 49, 2600– 2610, DOI: 10.1021/jm051144x
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There is no corresponding record for this reference.
.
(b) Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.; Hallett, D.; Merchant, K. J.; Thomas, S. R. 8-Fluoroimidazo[1,2-a]pyridine: synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABA_A receptor. Bioorg. Med. Chem. Lett. 2006, 16, 1518– 1522, DOI: 10.1016/j.bmcl.2005.12.037
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95b
8-Fluoroimidazo[1,2-a]pyridine: Synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptor
Humphries, Alexander C.; Gancia, Emanuela; Gilligan, Myra T.; Goodacre, Simon; Hallett, David; Merchant, Kevin J.; Thomas, Steve R.
Bioorganic & Medicinal Chemistry Letters (2006), 16 (6), 1518-1522CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochem. mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochem. mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 2'-fluoro-5'-[8-fluoro-7-(2-hydroxy-2-propyl)imidazo[1,2-a]pyridin-3-yl]biphenyl-2-carbonitrile acts as a bioisosteric replacement for imidazopyrimidine in the GABAA receptor modulator 2'-fluoro-5'-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile.
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96
(a) Robarge, K. D.; Lee, W.; Eigenbrot, C.; Ultsch, M.; Wiesmann, C.; Heald, R.; Price, S.; Hewitt, J.; Jackson, P.; Savy, P.; Burton, B.; Choo, E. F.; Pang, J.; Boggs, J.; Yang, A.; Yang, X.; Baumgardner, M. Structure based design of novel 6,5 heterocbicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a]pyrazine G-479. Bioorg. Med. Chem. Lett. 2014, 24, 4714– 4723, DOI: 10.1016/j.bmcl.2014.08.008
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There is no corresponding record for this reference.
97
(a) Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Yang, X.; Richards, M.; Shipps, G. W., Jr. Discovery of a novel series of CHK1 kinase inhibitors with a distinctive hinge binding mode. ACS Med. Chem. Lett. 2012, 3, 123– 128, DOI: 10.1021/ml200249h
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97a
Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode
Huang, Xiaohua; Cheng, Cliff C.; Fischmann, Thierry O.; Duca, Jose S.; Yang, Xianshu; Richards, Matthew; Shipps, Gerald W.
ACS Medicinal Chemistry Letters (2012), 3 (2), 123-128CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection-mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2.
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(b) Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Richards, M.; Tadikonda, P. K.; Reddy, P. A.; Zhao, L.; Siddiqui, M. A.; Parry, D.; Davis, N.; Seghezzi, W.; Wiswell, D.; Shipps, G. W., Jr. Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2590– 2594, DOI: 10.1016/j.bmcl.2013.02.108
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97b
Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors
Huang, Xiaohua; Cheng, Cliff C.; Fischmann, Thierry O.; Duca, Jose S.; Richards, Matthew; Tadikonda, Praveen K.; Reddy, Panduranga Adulla; Zhao, Lianyun; Arshad Siddiqui, M.; Parry, David; Davis, Nicole; Seghezzi, Wolfgang; Wiswell, Derek; Shipps, Gerald W.
Bioorganic & Medicinal Chemistry Letters (2013), 23 (9), 2590-2594CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
N-(Piperazinylaryl) amino- and heterocyclyl-substituted thiazolecarboxamides such as N-(piperazinylpyridinyl) (oxoisoindolinyl)thiazolecarboxamide I were prepd. as selective inhibitors of checkpoint kinase 1 (CHK1). Both the identities of the amino substituent on the thiazole ring and the aryl ring connecting the piperazine moiety to the thiazolecarboxamide were varied to det. the structure-activity relationship for enzymic and cellular CHK1 inhibition and for selectivity over the related kinase CHK2. I inhibited CHK1 with IC50 values against the enzyme and against cells of 1 nM and 30 nM, resp., with > 104 selectivity for CHK1 over CHK2; the inhibition of CYP 3A4, 2D6, and 2C9 in human liver microsomes, of hERG in various assays, and of other kinases and of various G protein-coupled receptors by I was detd. The structure of a complex of I with CHK1 was detd. by X-ray crystallog.; the topol. of its binding to the ATP-binding site of CHK1 is detd.
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98
(a) Koller, A. N.; Božilović, J.; Engels, J. W.; Gohlke, H. Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs. Nucleic Acids Res. 2010, 38, 3133– 3146, DOI: 10.1093/nar/gkp1237
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98a
Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs
Koller, Alrun N.; Bozilovic, Jelena; Engels, Joachim W.; Gohlke, Holger
Nucleic Acids Research (2010), 38 (9), 3133-3146CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
The thermodn. of base pairing is of fundamental importance. Fluorinated base analogs are valuable tools for investigating pairing interactions. To understand the influence of direct base-base interactions in relation to the role of water, pairing free energies between natural nucleobases and fluorinated analogs are estd. by potential of mean force calcns. Compared to pairing of AU and GC, pairing involving fluorinated analogs is unfavorable by 0.5-1.0 kcal mol-1. Decompg. the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs. These differences originate from direct base-base interactions and contributions of water. Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol-1 compared to non-fluorinated analogs. This is attributed to stabilizing C-F...H-N dipolar interactions and stronger N...H-C hydrogen bonds, demonstrating direct and indirect influences of fluorine. 7-Methyl-7H-purine and its 9-deaza analog (Z) have been suggested as members of a new class of non-fluorinated base analogs. Z is found to be the least destabilizing universal base in the context of RNA known to date. This is the first exptl. evidence for nitrogen-contg. heterocylces as bioisosteres of arom. rings bearing fluorine atoms.
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(b) Gohlke, H.; Božilović, J.; Engels, J. W. Synthesis and properties of fluorinated nucleobases in DNA and RNA. Mol. Medicine Med. Chem. 2012, 6, 3– 32, DOI: 10.1142/9781848166363_0001
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98b
Synthesis and properties of fluorinated nucleobases in DNA and RNA
Gohlke, Holger; Bozilovic, Jelena; Engels, Joachim W.
Molecular Medicine and Medicinal Chemistry (2012), 6 (Fluorine in Pharmaceutical and Medicinal Chemistry), 3-32CODEN: MMMCCE ISSN:. (Imperial College Press)
A review with refs. Synthesis and crystallog. studies of fluorinated non-polar nucleoside isosteres and thermodn. analyses and computer simulations of model DNA and RNAs incorporating them are reviewed.
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99
(a) Giroud, M.; Harder, M.; Kuhn, B.; Haap, W.; Trapp, N.; Schweizer, W. B.; Schirmeister, T.; Diederich, F. Fluorine scan of inhibitors of the cysteine protease human cathepsin L: dipolar and quadrupolar effects in the π-stacking of fluorinated phenyl rings on peptide amide bonds. ChemMedChem 2016, 11, 1042– 1047, DOI: 10.1002/cmdc.201600132
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99a
Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds
Giroud, Maude; Harder, Michael; Kuhn, Bernd; Haap, Wolfgang; Trapp, Nils; Schweizer, W. Bernd; Schirmeister, Tanja; Diederich, Francois
ChemMedChem (2016), 11 (10), 1042-1047CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chem. calcns. In the exptl. study, the Ph substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by addnl. interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calcns. strongly support the contributions of the mol. quadrupole moments of the fluorinated Ph rings to the π-stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π-stacking on protein amide fragments.
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(b) Giroud, M.; Ivkovic, J.; Martignoni, M.; Fleuti, M.; Trapp, N.; Haap, W.; Kuglstatter, A.; Benz, J.; Kuhn, B.; Schirmeister, T.; Diederich, F. Inhibition of the cysteine protease human cathepsin L by triazine nitriles: amide···heteroarene π-stacking interactions and chalcogen bonding in the S3 pocket. ChemMedChem 2017, 12, 257– 270, DOI: 10.1002/cmdc.201600563
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99b
Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide···Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket
Giroud, Maude; Ivkovic, Jakov; Martignoni, Mara; Fleuti, Marianne; Trapp, Nils; Haap, Wolfgang; Kuglstatter, Andreas; Benz, Joerg; Kuhn, Bernd; Schirmeister, Tanja; Diederich, Francois
ChemMedChem (2017), 12 (3), 257-270CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarene···peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory consts. (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroarom. ligands feature enhanced binding by comparison with hydrocarbon analogs. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nM) and benzothiazolyl (Ki=17 nM) ligands was enhanced by intermol. C-S···O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.
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100
Császár, P.; Császár, A. On the dipole moments of fluorobenzenes by quantum chemical methods. J. Mol. Struct.: THEOCHEM 1984, 110, 405– 407, DOI: 10.1016/0166-1280(84)80090-1
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There is no corresponding record for this reference.
101
van Niel, M. B.; Collins, I.; Beer, M. S.; Broughton, H. B.; Cheng, S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.; MacLeod, A. M.; Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.; Russell, M. G. N.; Sohal, B.; Stanton, J. A.; Thomas, S.; Verrier, H.; Watt, A. P.; Castro, J. L. Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1_D receptor ligands with improved pharmacokinetic profiles. J. Med. Chem. 1999, 42, 2087– 2104, DOI: 10.1021/jm981133m
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101
Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles and 3-(3-(1-piperazinyl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles
van Niel, Monique B.; Collins, Ian; Beer, Margaret S.; Broughton, Howard B.; Cheng, Susan K. F.; Goodacre, Simon C.; Heald, Anne; Locker, Karen L.; MacLeod, Angus M.; Morrison, Denise; Moyes, Christopher R.; O'Connor, Desmond; Pike, Andrew; Rowley, Michael; Russel, N.; Sohal, Balbinder; Stanton, Josephine A.; Thomas, Steven; Verrier, Hugh; Watt, Alan P.; Castro, Jose L.
Journal of Medicinal Chemistry (1999), 42 (12), 2087-2104CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
It has previously been reported that a 3-(3-(1-piperazinyl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal, versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivs. with one or two fluorines in the Pr linker were developed. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compds., and this redn. of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.
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102
(a) Paulini, R.; Müller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 1788– 1805, DOI: 10.1002/anie.200462213
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102a
Orthogonal multipolar interactions in structural chemistry and biology
Paulini, Ralph; Mueller, Klaus; Diederich, Francois
Angewandte Chemie, International Edition (2005), 44 (12), 1788-1805CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The past few decades of mol. recognition studies have greatly enhanced our knowledge on apolar, ion-dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biol. receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A no. of illustrative examples of these interactions found in X-ray crystal structures of small mols. and protein-ligand complexes demonstrate their propensity and thus potential importance for both, chem. and biol. mol. recognition processes.
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(b) Xing, L.; Keefer, C.; Brown, M. F. Fluorine multipolar interaction: towards elucidating its energetics in binding recognition. J. Fluorine Chem. 2017, 198, 47– 53, DOI: 10.1016/j.jfluchem.2016.12.013
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102b
Fluorine multipolar interaction: Toward elucidating its energetics in binding recognition
Xing, Li; Keefer, Christopher; Brown, Matthew F.
Journal of Fluorine Chemistry (2017), 198 (), 47-53CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
Multipolar interactions have gained attention due to their roles in mol. recognition events of chem. and biol. systems. Structural evidence suggests that the fluorine multipolar interaction is a favorable mol. interaction in the paradigm of protein-ligand recognition. With an aim to understand its propensity and energetics in ligand-protein assembly, the authors mined the "Pfizer protein-ligand x-ray structure database" with three-dimensional constraints for the presence of such interactions. A set of transformation rules were applied to generate their corresponding matched mol. pairs (MMPs) that bear hydrogen(s) in place of the interacting fluorine(s). Biol. activities were retrieved from the authors' internal data warehouse for the MMPs with and without the ability to form the multipolar interaction. On the basis of the obsd. potency differences the authors detd. that the free energy gain assocd. with the fluorine multipolar interaction is relatively modest, ∼0.3-0.6 kcal/mol, and the net impact on lipophilic efficiency (LipE) is essentially neutral. A general guideline for medicinal chemists has emerged from this study, enabling a more rational employment of this type of interaction in mol. design.
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103
(a) Shi, A.; Murai, M. J.; He, S.; Lund, G.; Hartley, T.; Purohit, T.; Reddy, G.; Chruszcz, M.; Grembecka, J.; Cierpicki, T. Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 2012, 120, 4461– 4469, DOI: 10.1182/blood-2012-05-429274
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103a
Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia
Shi, Aibin; Murai, Marcelo J.; He, Shihan; Lund, George; Hartley, Thomas; Purohit, Trupta; Reddy, Gireesh; Chruszcz, Maksymilian; Grembecka, Jolanta; Cierpicki, Tomasz
Blood (2012), 120 (23), 4461-4469CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)
Menin functions as a crit. oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resoln. crystal structure of human menin in complex with a small-mol. inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compd. binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compd. that binds to menin with low nanomolar affinity (Kd = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-mol. inhibitor.
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(b) Pollock, J.; Borkin, D.; Lund, G.; Purohit, T.; Dyguda-Kazimierowicz, E.; Grembecka, J.; Cierpicki, T. Rational design of orthogonal multipolar interactions with fluorine in protein–ligand complexes. J. Med. Chem. 2015, 58, 7465– 7474, DOI: 10.1021/acs.jmedchem.5b00975
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103b
Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein-Ligand Complexes
Pollock, Jonathan; Borkin, Dmitry; Lund, George; Purohit, Trupta; Dyguda-Kazimierowicz, Edyta; Grembecka, Jolanta; Cierpicki, Tomasz
Journal of Medicinal Chemistry (2015), 58 (18), 7465-7474CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Multipolar interactions involving fluorine and the protein backbone have been frequently obsd. in protein-ligand complexes. Such fluorine-backbone interactions may substantially contribute to the high affinity of small mol. inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin-MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogs by systematically changing the no. of fluorine atoms, and we detd. high-resoln. crystal structures of the complexes with menin. We found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin-MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine-backbone interactions in protein-ligand complexes, we developed a computational algorithm named FMAP, which calcs. fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Anal. of the menin-MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine-backbone interactions may represent a particularly attractive approach to improve inhibitors of protein-protein interactions.
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(c) Grembecka, J.; He, S.; Shi, A.; Purohit, T.; Muntean, A. G.; Sorenson, R. J.; Showalter, H. D.; Murai, M. J.; Belcher, A. M.; Hartley, T.; Hess, J. L.; Cierpicki, T. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 2012, 8, 277– 284, DOI: 10.1038/nchembio.773
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103c
Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia
Grembecka, Jolanta; He, Shihan; Shi, Aibin; Purohit, Trupta; Muntean, Andrew G.; Sorenson, Roderick J.; Showalter, Hollis D.; Murai, Marcelo J.; Belcher, Amalia M.; Hartley, Thomas; Hess, Jay L.; Cierpicki, Tomasz
Nature Chemical Biology (2012), 8 (3), 277-284CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-mol. inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compds. effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compds. provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.
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(d) Borkin, D.; Pollock, J.; Kempinska, K.; Purohit, T.; Li, X.; Wen, B.; Zhao, T.; Miao, H.; Shukla, S.; He, M.; Sun, D.; Cierpicki, T.; Grembecka, J. Property focused structure-based optimization of small molecule inhibitors of the protein–protein interaction between menin and mixed lineage leukemia (MLL). J. Med. Chem. 2016, 59, 892– 913, DOI: 10.1021/acs.jmedchem.5b01305
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103d
Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)
Borkin, Dmitry; Pollock, Jonathan; Kempinska, Katarzyna; Purohit, Trupta; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Miao, Hongzhi; Shukla, Shirish; He, Miao; Sun, Duxin; Cierpicki, Tomasz; Grembecka, Jolanta
Journal of Medicinal Chemistry (2016), 59 (3), 892-913CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Development of potent small mol. inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compds., which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compd. 1 (MI-136) to identify compds. suitable for in vivo studies in mice. This work resulted in the identification of compd. 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications.
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104
(a) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst-Sander, U.; D’Arcy, A.; Stihle, M.; Müller, K.; Diederich, F. A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F···C═O interactions. Angew. Chem., Int. Ed. 2003, 42, 2507– 2511, DOI: 10.1002/anie.200351268
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104a
A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: Evidence for C-F···C=O interactions
Olsen, Jacob A.; Banner, David W.; Seiler, Paul; Sander, Ulrike Obst; D'Arcy, Allan; Stihle, Martine; Mueller, Klaus; Diederich, Francois
Angewandte Chemie, International Edition (2003), 42 (22), 2507-2511CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A highly fluorophilic environment comprising the H-Cα-C=O unit of Asn 98 in the active site of thrombin was identified by X-ray crystallog. of a complex formed between the enzyme and a synthetic inhibitor (see partial X-ray structure, distances are in Angstroms). Short C-F···H-Cα and C-F···C=O contacts involving H-Cα-C=O fragments were also frequently obsd. in small-mol. X-ray crystal structures.
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(b) Olsen, J. A.; Banner, D. W.; Seiler, P.; Wagner, B.; Tschopp, T.; Obst-Sander, U.; Kansy, M.; Müller, K.; Diederich, F. Fluorine interactions at the thrombin active site: protein backbone fragments H-Cα-C═O comprise a favorable C-F environment and interactions of C-F with electrophiles. ChemBioChem 2004, 5, 666– 675, DOI: 10.1002/cbic.200300907
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104b
Fluorine interactions at the thrombin active site: Protein backbone fragments H-Cα-C=O comprise a favorable C-F environment and interactions of C-F with electrophiles
Olsen, Jacob A.; Banner, David W.; Seiler, Paul; Wagner, Bjoern; Tschopp, Thomas; Obst-Sander, Ulrike; Kansy, Manfred; Mueller, Klaus; Diederich, Francois
ChemBioChem (2004), 5 (5), 666-675CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
In a systematic fluorine scan of a rigid inhibitor to map the fluorophilicity/fluorophobicity of the active site in thrombin, one or more F substituents were introduced into the benzyl ring reaching into the D pocket. The 4-fluorobenzyl inhibitor showed a five to tenfold higher affinity than ligands with other fluorination patterns. X-ray crystal-structure anal. of the protein-ligand complex revealed favorable C-F···H-Cα-C=O and C-F···C=O interactions of the 4-F substituent of the inhibitor with the backbone H-Cα-C=O unit of Asn98. The importance of these interactions was further corroborated by the anal. of small-mol. X-ray crystal-structure searches in the Protein Data Base (PDB) and the Cambridge Structural Database (CSD). In the C-F···C=O interactions that are obsd. for both arom. and aliph. C-F units and a variety of carbonyl and carboxyl derivs., the F atom approaches the C=O C atom preferentially along the pseudotrigonal axis of the carbonyl system. Similar orientational preferences are also seen in the dipolar interactions C-F···C≡N, C-F···C-F1 and C-F···NO2, in which the F atoms interact at subvan der Waals distances with the electrophilic centers.
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(c) Schweizer, E.; Hoffmann-Röder, A.; Olsen, J. A.; Seiler, P.; Obst-Sander, U.; Wagner, B.; Kansy, M.; Banner, D. W.; Diederich, F. Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors. Org. Biomol. Chem. 2006, 4, 2364– 2375, DOI: 10.1039/B602585D
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105
Bauer, M. R.; Jones, R. N.; Baud, M. G. J.; Wilcken, R.; Boeckler, F. M.; Fersht, A. R.; Joerger, A. C.; Spencer, J. Harnessing fluorine-sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs. ACS Chem. Biol. 2016, 11, 2265– 2274, DOI: 10.1021/acschembio.6b00315
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105
Harnessing Fluorine-Sulfur Contacts and Multipolar Interactions for the Design of p53 Mutant Y220C Rescue Drugs
Bauer, Matthias R.; Jones, Rhiannon N.; Baud, Matthias G. J.; Wilcken, Rainer; Boeckler, Frank M.; Fersht, Alan R.; Joerger, Andreas C.; Spencer, John
ACS Chemical Biology (2016), 11 (8), 2265-2274CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-mol. stabilizers of this mutant. One of these mols., PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 μM, thereby increasing the melting temp. of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small mol. ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine-protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole Et anchor, which is deeply buried within the binding site in the Y220C-PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol-1 atom-1). High-resoln. crystal structures of the Y220C-ligand complexes combined with quantum chem. calcns. revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein-fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells.
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106
(a) Lou, Y.; Sweeney, Z. K.; Kuglstatter, A.; Davis, D.; Goldstein, D. M.; Han, X.; Hong, J.; Kocer, B.; Kondru, R. K.; Litman, R.; McIntosh, J.; Sarma, K.; Suh, J.; Taygerly, J.; Owens, T. D. Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s tyrosine kinase (BTK) inhibitor scaffold. Bioorg. Med. Chem. Lett. 2015, 25, 367– 371, DOI: 10.1016/j.bmcl.2014.11.030
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106a
Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold
Lou, Yan; Sweeney, Zachary K.; Kuglstatter, Andreas; Davis, Dana; Goldstein, David M.; Han, Xiaochun; Hong, Junbae; Kocer, Buelent; Kondru, Rama K.; Litman, Renee; McIntosh, Joel; Sarma, Keshab; Suh, Judy; Taygerly, Joshua; Owens, Timothy D.
Bioorganic & Medicinal Chemistry Letters (2015), 25 (2), 367-371CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a satd. bicyclic ring system yields no apparent benefit, the same operation on an unsatd. bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent mols. and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.
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(b) Lou, Y.; Han, X.; Kuglstatter, A.; Kondru, R. K.; Sweeney, Z. K.; Soth, M.; McIntosh, J.; Litman, R.; Suh, J.; Kocer, B.; Davis, D.; Park, J.; Frauchiger, S.; Dewdney, N.; Zecic, H.; Taygerly, J. P.; Sarma, K.; Hong, J.; Hill, R. J.; Gabriel, T.; Goldstein, D. M.; Owens, T. D. Structure-based drug design of RN486, a potent and selective Bruton’s tyrosine kinase (BTK) Inhibitor, for the treatment of rheumatoid arthritis. J. Med. Chem. 2015, 58, 512– 516, DOI: 10.1021/jm500305p
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106b
Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis
Lou, Yan; Han, Xiaochun; Kuglstatter, Andreas; Kondru, Rama K.; Sweeney, Zachary K.; Soth, Michael; McIntosh, Joel; Litman, Renee; Suh, Judy; Kocer, Buelent; Davis, Dana; Park, Jaehyeon; Frauchiger, Sandra; Dewdney, Nolan; Zecic, Hasim; Taygerly, Joshua P.; Sarma, Keshab; Hong, Junbae; Hill, Ronald J.; Gabriel, Tobias; Goldstein, David M.; Owens, Timothy D.
Journal of Medicinal Chemistry (2015), 58 (1), 512-516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alc. group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compd. I (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclin. characterization based on its favorable properties.
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(c) Lou, Y.; Lopez, F.; Jiang, Y.; Han, X.; Brotherton, C.; Billedeau, R.; Gabriel, S.; Gleason, S.; Goldstein, D. M.; Hilgenkamp, R.; Kocer, B.; Orzechowski, L.; Tan, J.; Wovkulich, P.; Wen, B.; Fry, D.; Di Lello, P.; Chen, L.; Zhang, F.-j.; Fretland, J.; Nangia, A.; Yang, T.; Owens, T. D. Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton’s tyrosine kinase (BTK). Bioorg. Med. Chem. Lett. 2017, 27, 632– 635, DOI: 10.1016/j.bmcl.2016.11.092
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106c
Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK)
Lou, Yan; Lopez, Francisco; Jiang, Yongying; Han, Xiaochun; Brotherton, Chris; Billedeau, Roland; Gabriel, Steve; Gleason, Shelly; Goldstein, David M.; Hilgenkamp, Ramona; Kocer, Buelent; Orzechowski, Lucja; Tan, Jenny; Wovkulich, Peter; Wen, Bo; Fry, David; Di Lello, Paola; Chen, Lucy; Zhang, Fang-jie; Fretland, Jennifer; Nangia, Anjali; Yang, Tian; Owens, Timothy D.
Bioorganic & Medicinal Chemistry Letters (2017), 27 (3), 632-635CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a no. of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead mols. in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compd. 1 has a value of 459 pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation assocn. of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS anal. of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compd. 7 (RN941) with significantly reduced covalent binding of 26 pmol/mg protein.
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107
Hao, G.-F.; Wang, F.; Li, H.; Zhu, X.-L.; Yang, W.-C.; Huang, L.-S.; Wu, J.-W.; Berry, E. A.; Yang, G.-F. Computational discovery of picomolar Q_o site inhibitors of cytochrome bc₁ complex. J. Am. Chem. Soc. 2012, 134, 11168– 11176, DOI: 10.1021/ja3001908
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107
Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 Complex
Hao, Ge-Fei; Wang, Fu; Li, Hui; Zhu, Xiao-Lei; Yang, Wen-Chao; Huang, Li-Shar; Wu, Jia-Wei; Berry, Edward A.; Yang, Guang-Fu
Journal of the American Chemical Society (2012), 134 (27), 11168-11176CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A crit. challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophys. method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Qo site inhibitors of the cytochrome bc1 complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compd. 4 (Ki = 881.80 nM, porcine bc1), the most potent compd. 4f displayed 20 507-fold improved binding affinity (Ki = 43.00 pM). Compd. 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Addnl., the crystal structure of compd. 4e (Ki = 83.00 pM) bound to the chicken bc1 was detd. at 2.70 Å resoln., providing a mol. basis for understanding its ultrapotency. To the authors' knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophys. screening techniques.
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108
García-LLinás, X.; Bauzá, A.; Seth, S. K.; Frontera, A. Importance of R-CF₃•••O tetrel bonding interactions in biological systems. J. Phys. Chem. A 2017, 121, 5371– 5376, DOI: 10.1021/acs.jpca.7b06052
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There is no corresponding record for this reference.
109
Cisneros, J. A.; Robertson, M. J.; Valhondo, M.; Jorgensen, W. L. Irregularities in enzyme assays: the case of macrophage migration inhibitory factor. Bioorg. Med. Chem. Lett. 2016, 26, 2764– 2767, DOI: 10.1016/j.bmcl.2016.04.074
[Crossref], [PubMed], [CAS], Google Scholar
109
Irregularities in enzyme assays: The case of macrophage migration inhibitory factor
Cisneros, Jose A.; Robertson, Michael J.; Valhondo, Margarita; Jorgensen, William L.
Bioorganic & Medicinal Chemistry Letters (2016), 26 (12), 2764-2767CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Inhibitors of human macrophage migration inhibitory factor (MIF) previously reported in the literature have been reexamd. by synthesis, assaying for tautomerase activity, and protein crystallog. Substantial inconsistencies between prior and current assay results are noted. They appear to arise from difficulties with the tautomerase substrates, soly. issues, and esp. covalent inhibition. Incubation time variation shows that several compds. are covalent or slow-binding inhibitors. Two protein crystal structures are provided; one confirms that a twice-discovered compd. is a covalent inhibitor.
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110
(a) Wang, F.; Travins, J.; DeLaBarre, B.; Penard-Lacronique, V.; Schalm, S.; Hansen, E.; Straley, K.; Kernytsky, A.; Liu, W.; Gliser, C.; Yang, H.; Gross, S.; Artin, E.; Saada, V.; Mylonas, E.; Quivoron, C.; Popovici-Muller, J.; Saunders, J. O.; Salituro, F. G.; Yan, S.; Murray, S.; Wei, W.; Gao, Y.; Dang, L.; Dorsch, M.; Agresta, S.; Schenkein, D. P.; Biller, S. A.; Su, S. M.; de Botton, S.; Yen, K. E. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013, 340, 622– 626, DOI: 10.1126/science.1234769
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110a
Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation
Wang, Fang; Travins, Jeremy; De La Barre, Byron; Penard-Lacronique, Virginie; Schalm, Stefanie; Hansen, Erica; Straley, Kimberly; Kernytsky, Andrew; Liu, Wei; Gliser, Camelia; Yang, Hua; Gross, Stefan; Artin, Erin; Saada, Veronique; Mylonas, Elena; Quivoron, Cyril; Popovici-Muller, Janeta; Saunders, Jeffrey O.; Salituro, Francesco G.; Yan, Shunqi; Murray, Stuart; Wei, Wentao; Gao, Yi; Dang, Lenny; Dorsch, Marion; Agresta, Sam; Schenkein, David P.; Biller, Scott A.; Su, Shinsan M.; de Botton, Stephane; Yen, Katharine E.
Science (Washington, DC, United States) (2013), 340 (6132), 622-626CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
A no. of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small mol., AGI-6780, that potently and selectively inhibits the tumor-assocd. mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymol. anal. were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
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(b) Yen, K.; Travins, J.; Wang, F.; David, M. D.; Artin, E.; Straley, K.; Padyana, A.; Gross, S.; DeLaBarre, B.; Tobin, E.; Chen, Y.; Nagaraja, R.; Choe, S.; Jin, L.; Konteatis, Z.; Cianchetta; Saunders, J. O.; Salituro, F. G.; Quivoron, C.; Opolon, P.; Bawa, O.; Saada, O.; Paci, A.; Broutin, S.; Bernard, O. A.; de Botton, S.; Marteyn, B. S.; Pilichowska, M.; Xu, Y. X.; Fang, C.; Jiang, F.; Wei, W.; Jin, S.; Silverman, L.; Liu, W.; Yang, H.; Dang, L.; Dorsch, M.; Penard-Lacronique, V.; Biller, S. A.; Su, S.-S. M. AG-221, A first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discovery 2017, 7, 478– 493, DOI: 10.1158/2159-8290.CD-16-1034
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110b
AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
Yen, Katharine; Travins, Jeremy; Wang, Fang; David, Muriel D.; Artin, Erin; Straley, Kimberly; Padyana, Anil; Gross, Stefan; De La Barre, Byron; Tobin, Erica; Chen, Yue; Nagaraja, Raj; Choe, Sung; Jin, Lei; Konteatis, Zenon; Cianchetta, Giovanni; Saunders, Jeffrey O.; Salituro, Francesco G.; Quivoron, Cyril; Opolon, Paule; Bawa, Olivia; Saada, Veronique; Paci, Angelo; Broutin, Sophie; Bernard, Olivier A.; de Botton, Stephane; Marteyn, Benoit S.; Pilichowska, Monika; Xu, Ying Xia; Fang, Cheng; Jiang, Fan; Wei, Wentao; Jin, Shengfang; Silverman, Lee; Liu, Wei; Yang, Hua; Dang, Lenny; Dorsch, Marion; Penard-Lacronique, Virginie; Biller, Scott A.; Su, Shin-San Michael
Cancer Discovery (2017), 7 (5), 478-493CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)
Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematol. and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG prodn. and induced cellular differentiation in primary human IDH2 mutation-pos. acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clin. trials of AG-221 in patients with IDH2 mutation-pos. advanced hematol. malignancies. Significance: Mutations in IDH1/2 are identified in approx. 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclin. models and induces differentiation of malignant blasts, supporting its clin. development.
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111
Bhatia, C.; Yue, W. W.; Niesen, F.; Pilka, E.; Ugochukwu, E.; Savitsky, P.; Hozjan, V.; Roos, A. K.; Filippakopoulos, P.; Von Delft, F.; Heightman, T.; Arrowsmith, C.; Weigelt, J.; Edwards, A.; Bountra, C.; Opperman, U. 2WM3: Crystal structure of NmrA-like family domain containing protein 1 in complex with niflumic acid. Protein Data Bank, 2009, DOI: DOI: 10.2210/pdb2wm3/pdb .
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112
Blobaum, A. L.; Uddin, Md. J.; Felts, A. S.; Crews, B. C.; Rouzer, C. A.; Marnett, L. J. The 2′-trifluoromethyl analogue of indomethacin is a potent and selective COX-2 inhibitor. ACS Med. Chem. Lett. 2013, 4, 486– 490, DOI: 10.1021/ml400066a
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113
Sun, L.-Q.; Mull, E.; Zheng, B.; D’Andrea, S.; Zhao, Q.; Wang, A. X.; Sin, N.; Venables, B. L.; Sit, S.-Y.; Chen, Y.; Chen, J.; Cocuzza, A.; Bilder, D. M.; Mathur, A.; Rampulla, R.; Chen, B.-C.; Palani, T.; Ganesan, S.; Arunachalam, P. N.; Falk, P.; Levine, A.; Chen, C.; Friborg, J.; Yu, F.; Hernandez, D.; Sheaffer, A. K.; Knipe, J. O.; Han, Y.-H.; Schartman, R.; Donoso, M.; Mosure, K.; Sinz, M. W.; Zvyaga, T.; Rajamani, R.; Kish, K.; Tredup, J.; Klei, H. E.; Gao, Q.; Ng, A.; Mueller, L.; Grasela, D. M.; Adams, S.; Loy, J.; Levesque, P. C.; Sun, H.; Shi, H.; Sun, L.; Warner, W.; Li, D.; Zhu, J.; Wang, Y.-K.; Fang, H.; Cockett, M. I.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Discovery of a potent acyclic, tripeptidic, acyl sulfonamide inhibitor of hepatitis C virus NS3 protease as a back-up to asunaprevir with the potential for once-daily dosing. J. Med. Chem. 2016, 59, 8042– 8060, DOI: 10.1021/acs.jmedchem.6b00821
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113
Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing
Sun, Li-Qiang; Mull, Eric; Zheng, Barbara; D'Andrea, Stanley; Zhao, Qian; Wang, Alan Xiangdong; Sin, Ny; Venables, Brian L.; Sit, Sing-Yuen; Chen, Yan; Chen, Jie; Cocuzza, Anthony; Bilder, Donna M.; Mathur, Arvind; Rampulla, Richard; Chen, Bang-Chi; Palani, Theerthagiri; Ganesan, Sivakumar; Arunachalam, Pirama Nayagam; Falk, Paul; Levine, Steven; Chen, Chaoqun; Friborg, Jacques; Yu, Fei; Hernandez, Dennis; Sheaffer, Amy K.; Knipe, Jay O.; Han, Yong-Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael W.; Zvyaga, Tatyana; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E.; Gao, Qi; Ng, Alicia; Mueller, Luciano; Grasela, Dennis M.; Adams, Stephen; Loy, James; Levesque, Paul C.; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, William; Li, Danshi; Zhu, Jialong; Wang, Ying-Kai; Fang, Hua; Cockett, Mark I.; Meanwell, Nicholas A.; McPhee, Fiona; Scola, Paul M.
Journal of Medicinal Chemistry (2016), 59 (17), 8042-8060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir is described. The objective of this work was the identification of a drug with antiviral properties and toxicol. parameters similar to asunaprevir, but with a preclin. pharmacokinetic (PK) profile that was predictive of once-daily dosing. Crit. to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compds. that, like asunaprevir, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 from clin. trials. Structure-activity relationships (SARs) at each of the structural subsites in asunaprevir were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Addnl. modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 I.
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(a) Phillips, M. A.; Gujjar, R.; Malmquist, N. A.; White, J.; El Mazouni, F.; Baldwin, J.; Rathod, P. K. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite, Plasmodium falciparum. J. Med. Chem. 2008, 51, 3649– 3653, DOI: 10.1021/jm8001026
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114a
Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitors with Potent and Selective Activity against the Malaria Parasite Plasmodium falciparum
Phillips, Margaret A.; Gujjar, Ramesh; Malmquist, Nicholas A.; White, John; El Mazouni, Farah; Baldwin, Jeffrey; Rathod, Pradipsinh K.
Journal of Medicinal Chemistry (2008), 51 (12), 3649-3653CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor I that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogs were produced by an inexpensive three-step synthesis, and the series showed good assocn. between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC50 = 79 nM).
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(b) Gujjar, R.; Marwaha, A.; El Mazouni, F.; White, J.; White, K. L.; Creason, S.; Shackleford, D. M.; Baldwin, J.; Charman, W. N.; Buckner, F. S.; Charman, S.; Rathod, P. K.; Phillips, M. A. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J. Med. Chem. 2009, 52, 1864– 1872, DOI: 10.1021/jm801343r
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114b
Identification of a Metabolically Stable Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Antimalarial Activity in Mice
Gujjar, Ramesh; Marwaha, Alka; El Mazouni, Farah; White, John; White, Karen L.; Creason, Sharon; Shackleford, David M.; Baldwin, Jeffrey; Charman, William N.; Buckner, Frederick S.; Charman, Susan; Rathod, Pradipsinh K.; Phillips, Margaret A.
Journal of Medicinal Chemistry (2009), 52 (7), 1864-1872CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compds. contg. naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metab. in human liver microsomes and which showed prolonged exposure in mice. Compd. 21 (DSM74), contg. p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.
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(c) Deng, X.; Gujjar, R.; El Mazouni, F.; Kaminsky, W.; Malmquist, N. A.; Goldsmith, E. J.; Rathod, P. K.; Phillips, M. A. Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J. Biol. Chem. 2009, 284, 26999– 27009, DOI: 10.1074/jbc.M109.028589
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114c
Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds
Deng, Xiaoyi; Gujjar, Ramesh; El Mazouni, Farah; Kaminsky, Werner; Malmquist, Nicholas A.; Goldsmith, Elizabeth J.; Rathod, Pradipsinh K.; Phillips, Margaret A.
Journal of Biological Chemistry (2009), 284 (39), 26999-27009CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure detn. of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chem. classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small mol. crystallog., is that the triazolopyrimidines populate a resonance form that promotes charge sepn. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into species-selective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.
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(d) Coteron, J. M.; Marco, M.; Esquivias, J.; Deng, X.; White, K. L.; White, J.; Koltun, M.; El Mazouni, F.; Kokkonda, S.; Katneni, K.; Bhamidipati, R.; Shackleford, D. M.; Angulo-Barturen, I.; Ferrer, S. B.; Jiménez-Díaz, M. B.; Gamo, F.-J.; Goldsmith, E. J.; Charman, W. N.; Bathurst, I.; Floyd, D.; Matthews, D.; Burrows, J. N.; Rathod, P. K.; Charman, S. A.; Phillips, M. A. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J. Med. Chem. 2011, 54, 5540– 5561, DOI: 10.1021/jm200592f
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114d
Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential
Coteron, Jose M.; Marco, Maria; Esquivias, Jorge; Deng, Xiaoyi; White, Karen L.; White, John; Koltun, Maria; El Mazouni, Farah; Kokkonda, Sreekanth; Katneni, Kasiram; Bhamidipati, Ravi; Shackleford, David M.; Angulo-Barturen, Inigo; Ferrer, Santiago B.; Jimenez-Diaz, Maria Belen; Gamo, Francisco-Javier; Goldsmith, Elizabeth J.; Charman, William N.; Bathurst, Ian; Floyd, David; Matthews, David; Burrows, Jeremy N.; Rathod, Pradipsinh K.; Charman, Susan A.; Phillips, Margaret A.
Journal of Medicinal Chemistry (2011), 54 (15), 5540-5561CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chem. program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compd. has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compd. toward clin. candidate status.
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(e) Deng, X.; Kokkonda, S.; El Mazouni, F.; White, J.; Burrows, J. N.; Kaminsky, W.; Charman, S. A.; Matthews, D.; Rathod, P. K.; Phillips, M. A. Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. J. Med. Chem. 2014, 57, 5381– 5394, DOI: 10.1021/jm500481t
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114e
Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors
Deng, Xiaoyi; Kokkonda, Sreekanth; El Mazouni, Farah; White, John; Burrows, Jeremy N.; Kaminsky, Werner; Charman, Susan A.; Matthews, David; Rathod, Pradipsinh K.; Phillips, Margaret A.
Journal of Medicinal Chemistry (2014), 57 (12), 5381-5394CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. The authors describe a detailed anal. of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. The authors show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. The authors conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. The authors' studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
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(f) Phillips, M. A.; Lotharius, J.; Marsh, K.; White, J.; Dayan, A.; White, K. L.; Njoroge, J. W.; El Mazouni, F.; Lao, Y.; Kokkonda, S.; Tomchick, D. R.; Deng, X.; Laird, T.; Bhatia, S. N.; March, S.; Ng, C. L.; Fidock, D. A.; Wittlin, S.; Lafuente-Monasterio, M.; Benito, F. J.; Alonso, L. M.; Martinez, M. S.; Jimenez-Diaz, M. B.; Bazaga, S. F.; Angulo-Barturen, I.; Haselden, J. N.; Louttit, J.; Cui, Y.; Sridhar, A.; Zeeman, A. M.; Kocken, C.; Sauerwein, R.; Dechering, K.; Avery, V. M.; Duffy, S.; Delves, M.; Sinden, R.; Ruecker, A.; Wickham, K. S.; Rochford, R.; Gahagen, J.; Iyer, L.; Riccio, E.; Mirsalis, J.; Bathhurst, I.; Rueckle, T.; Ding, X.; Campo, B.; Leroy, D.; Rogers, M. J.; Rathod, P. K.; Burrows, J. N.; Charman, S. A. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci. Transl. Med. 2015, 7 (296), 296ra111, DOI: 10.1126/scitranslmed.aaa6645
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There is no corresponding record for this reference.
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(g) Phillips, M. A.; White, K. L.; Kokkonda, S.; Deng, X.; White, J.; El Mazouni, F.; Marsh, K.; Tomchick, D. R.; Manjalanagara, K.; Rudra, K. R.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Shackleford, D. M.; Chiu, F. C. K. M.; Campbell, M.; Jimenez-Diaz, M. B.; Ferrer Bazaga, S.; Angulo-Barturen, I.; Santos Martinez, M.; Lafuente-Monasterio, M.; Kaminsky, W.; Silue, K.; Zeeman, A.-M.; Kocken, C.; Leroy, D.; Blasco, B.; Rossignol, E.; Rueckle, T.; Matthews, D.; Burrows, J. N.; Waterson, D.; Palmer, M. J.; Rathod, P. K.; Charman, S. A. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. ACS Infect. Dis. 2016, 2, 945– 957, DOI: 10.1021/acsinfecdis.6b00144
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114g
A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria
Phillips, Margaret A.; White, Karen L.; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; El Mazouni, Farah; Marsh, Kennan; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N.; Marfurt, Jutta; Shackleford, David M.; Chiu, Francis C. K.; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Inigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N.; Waterson, David; Palmer, Michael J.; Rathod, Pradipsinh K.; Charman, Susan A.
ACS Infectious Diseases (2016), 2 (12), 945-957CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
The emergence of drug resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria and a selective inhibitor I of the Plasmodium enzyme is currently in clin. development. With the goal of identifying a backup compd. to I, the authors explored replacement of the SF5-aniline moiety of I with a series of CF3-pyridinyls, while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of II, which has improved soly., lower intrinsic clearance and increased plasma exposure after oral dosing compared to I, while maintaining a long predicted human half-life. Its improved phys. and chem. properties will allow it to be formulated more readily than I. II showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly II showed equal activity against both P. falciparum and P. vivax field isolates, while I was more active on P. falciparum. II has the potential to be developed as a single dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria leading to its advancement as a preclin. development candidate.
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115
Martin, M. P.; Zhu, J.-Y.; Lawrence, H. R.; Pireddu, R.; Luo, Y.; Alam, R.; Ozcan, S.; Sebti, S. M.; Lawrence, N. J.; Schönbrunn, E. A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A. ACS Chem. Biol. 2012, 7, 698– 706, DOI: 10.1021/cb200508b
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115
A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora A
Martin, Mathew P.; Zhu, Jin-Yi; Lawrence, Harshani R.; Pireddu, Roberta; Luo, Yunting; Alam, Riazul; Ozcan, Sevil; Sebti, Said M.; Lawrence, Nicholas J.; Schonbrunn, Ernst
ACS Chemical Biology (2012), 7 (4), 698-706CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
Most protein kinases share a DFG (Asp-Phe-Gly) motif in the ATP site that can assume two distinct conformations, the active DFG-in and the inactive DFG-out states. Small mol. inhibitors able to induce the DFG-out state have received considerable attention in kinase drug discovery. Using a typical DFG-in inhibitor scaffold of Aurora A, a kinase involved in the regulation of cell division, we found that halogen and nitrile substituents directed at the N-terminally flanking residue Ala273 induced global conformational changes in the enzyme, leading to DFG-out inhibitors that are among the most potent Aurora A inhibitors reported to date. The data suggest an unprecedented mechanism of action, in which induced-dipole forces along the Ala273 side chain alter the charge distribution of the DFG backbone, allowing the DFG to unwind. As the ADFG sequence and three-dimensional structure is highly conserved, DFG-out inhibitors of other kinases may be designed by specifically targeting the flanking alanine residue with elec. dipoles.
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(a) Clark, J.; Perrin, D. D. Prediction of the strengths of organic bases. Q. Rev., Chem. Soc. 1964, 18, 295– 320, DOI: 10.1039/qr9641800295
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116a
Prediction of the strengths of organic bases
Clark, Jim; Perrin, D. D.
(1964), 18 (3), 295-320 ISSN:.
A review with 44 references.
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(b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059
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116b
Predicting and tuning physicochemical properties in lead optimization: amine basicities
Morgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, Klaus
ChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
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117
Grunewald, G. L.; Seim, M. R.; Lu, J.; Makboul, M.; Criscione, K. R. Application of the Goldilocks effect to the design of potent and selective inhibitors of phenylethanolamine N-methyltransferase: balancing pK_a and steric effects in the optimization of 3-methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-fluorination. J. Med. Chem. 2006, 49, 2939– 2952, DOI: 10.1021/jm051262k
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117
Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination
Grunewald, Gary L.; Seim, Mitchell R.; Lu, Jian; Makboul, Mariam; Criscione, Kevin R.
Journal of Medicinal Chemistry (2006), 49 (10), 2939-2952CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α2-adrenoceptor. Fluorination of the Me group lowers the pKa of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pKa results in a redn. in affinity for the α2-adrenoceptor. However, increased fluorination also results in a redn. in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochem. evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often nonselective due to significant affinity for the α2-adrenoceptor, while the latter were devoid of α2-adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pKa properties and thus have enhanced selectivity vs. the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency vs. the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the "Goldilocks Effect" analogy, the 3-fluoromethyl-THIQs are too potent (too hot) at the α2-adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α2-adrenoceptor. This seems to be the first successful use of the β-fluorination of aliph. amines to impart selectivity to a pharmacol. agent while maintaining potency at the site of interest.
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Spahn, V.; Del Vecchio, G.; Labuz, D.; Rodriguez-Gaztelumendi, A.; Massaly, N.; Temp, J.; Durmaz, V.; Sabri, P.; Reidelbach, M.; Machelska, H.; Weber, M.; Stein, C. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 2017, 355, 966– 969, DOI: 10.1126/science.aai8636
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118
A nontoxic pain killer designed by modeling of pathological receptor conformations
Spahn, V.; Del Vecchio, G.; Labuz, D.; Rodriguez-Gaztelumendi, A.; Massaly, N.; Temp, J.; Durmaz, V.; Sabri, P.; Reidelbach, M.; Machelska, H.; Weber, M.; Stein, C.
Science (Washington, DC, United States) (2017), 355 (6328), 966-969CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathol. (rather than physiol.) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissocn. const., selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissocn. by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.
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(a) Cox, C. D.; Coleman, P. J.; Breslin, M. J.; Whitman, D. B.; Garbaccio, R. M.; Fraley, M. E.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Schaber, M. D.; Lobell, R. B.; Tao, W.; Davide, J. P.; Diehl, R. E.; Abrams, M. T.; South, V. J.; Huber, H. E.; Torrent, M.; Prueksaritanont, T.; Li, C.; Slaughter, D. E.; Mahan, E.; Fernandez-Metzler, C.; Yan, Y.; Kuo, L. C.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J. Med. Chem. 2008, 51, 4239– 4252, DOI: 10.1021/jm800386y
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119a
Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer
Cox, Christopher D.; Coleman, Paul J.; Breslin, Michael J.; Whitman, David B.; Garbaccio, Robert M.; Fraley, Mark E.; Buser, Carolyn A.; Walsh, Eileen S.; Hamilton, Kelly; Schaber, Michael D.; Lobell, Robert B.; Tao, Weikang; Davide, Joseph P.; Diehl, Ronald E.; Abrams, Marc T.; South, Vicki J.; Huber, Hans E.; Torrent, Maricel; Prueksaritanont, Thomayant; Li, Chunze; Slaughter, Donald E.; Mahan, Elizabeth; Fernandez-Metzler, Carmen; Yan, Youwei; Kuo, Lawrence C.; Kohl, Nancy E.; Hartman, George D.
Journal of Medicinal Chemistry (2008), 51 (14), 4239-4252CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations assocd. with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor (11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compds. from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that β-fluorination modulated the pKa of the piperidine nitrogen and reduced Pgp efflux, but the resulting compd. (14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compd. 30 that has an optimal in vitro and metabolic profile. Compd. 30 (MK-0731) was recently studied in a phase I clin. trial in patients with taxane-refractory solid tumors.
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(b) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Coleman, P. J.; Garbaccio, R. M.; Fraley, M. E.; Zrada, M. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Abrams, M. T.; South, V. J.; Huber, H. E.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part V: discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein. Bioorg. Med. Chem. Lett. 2007, 17, 2697– 2702, DOI: 10.1016/j.bmcl.2007.03.006
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120
McDonald, I. M.; Mate, R. A.; Zusi, F. C.; Huang, H.; Post-Munson, D. J.; Ferrante, M. A.; Gallagher, L.; Bertekap, R. L., Jr.; Knox, R. J.; Robertson, B. J.; Harden, D. G.; Morgan, D. G.; Lodge, N. J.; Dworetzky, S. I.; Olson, R. E.; Macor, J. E. Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists. Bioorg. Med. Chem. Lett. 2013, 23, 1684– 1688, DOI: 10.1016/j.bmcl.2013.01.070
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121
Sun, H.; Xia, M.; Shahane, S. A.; Jadhav, A.; Austin, C. P.; Huang, R. Are hERG channel blockers also phospholipidosis inducers?. Bioorg. Med. Chem. Lett. 2013, 23, 4587– 4590, DOI: 10.1016/j.bmcl.2013.06.034
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121
Are hERG channel blockers also phospholipidosis inducers?
Sun, Hongmao; Xia, Menghang; Shahane, Sampada A.; Jadhav, Ajit; Austin, Christopher P.; Huang, Ruili
Bioorganic & Medicinal Chemistry Letters (2013), 23 (16), 4587-4590CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Both pharmacophore models of the human ether-a-go-go-related gene (hERG) channel blockers and phospholipidosis (PLD) inducers contain a hydrophobic moiety and a hydrophilic motif/pos. charged center, so it is interesting to investigate the overlap between the ligand chem. spaces of both targets. The authors have assayed over 4000 non-redundant drug-like compds. for both their hERG inhibitory activity and PLD inducing potential in a quant. high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compds. identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compds. were pos. charged. Among the 48 compds. that induced PLD without inhibiting hERG channel, 24 compds. (50.0%) carried steroidal structures. According to the authors' results, hERG channel blockers and PLD inducers share a large chem. space. In addn., a pos. charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker.
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122
Nakajima, Y.; Inoue, T.; Nakai, K.; Mukoyoshi, K.; Hamaguchi, H.; Hatanaka, K.; Sasaki, H.; Tanaka, A.; Takahashi, F.; Kunikawa, S.; Usuda, H.; Moritomo, A.; Higashi, Y.; Inami, M.; Shirakami, S. Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3. Bioorg. Med. Chem. 2015, 23, 4871– 4883, DOI: 10.1016/j.bmc.2015.05.034
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122
Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3
Nakajima, Yutaka; Inoue, Takayuki; Nakai, Kazuo; Mukoyoshi, Koichiro; Hamaguchi, Hisao; Hatanaka, Keiko; Sasaki, Hiroshi; Tanaka, Akira; Takahashi, Fumie; Kunikawa, Shigeki; Usuda, Hiroyuki; Moritomo, Ayako; Higashi, Yasuyuki; Inami, Masamichi; Shirakami, Shohei
Bioorganic & Medicinal Chemistry (2015), 23 (15), 4871-4883CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivs. are promising candidates for treating such diseases. In chem. modification of lead compd. (I), the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addn., modulation of phys. properties such as mol. lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. The authors' optimization study gave compd. 31 (4-[[(3S,4R)-1-(5-cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide), which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
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123
Rombouts, F. J. R.; Tresadern, G.; Delgado, O.; Martínez-Lamenca, C.; Van Gool, M.; García-Molina, A.; Alonso de Diego, S. A.; Oehlrich, D.; Prokopcova, H.; Alonso, J. M.; Austin, N.; Borghys, H.; Van Brandt, S.; Surkyn, M.; De Cleyn, M.; Vos, A.; Alexander, R.; Macdonald, G.; Moechars, D.; Gijsen, H.; Trabanco, A. A. 1,4-Oxazine β-secretase 1 (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads. J. Med. Chem. 2015, 58, 8216– 8235, DOI: 10.1021/acs.jmedchem.5b01101
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123
1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads
Rombouts, Frederik J. R.; Tresadern, Gary; Delgado, Oscar; Martinez-Lamenca, Carolina; Van Gool, Michiel; Garcia-Molina, Aranzazu; Alonso de Diego, Sergio A.; Oehlrich, Daniel; Prokopcova, Hana; Alonso, Jose Manuel; Austin, Nigel; Borghys, Herman; Van Brandt, Sven; Surkyn, Michel; De Cleyn, Michel; Vos, Ann; Alexander, Richard; Macdonald, Gregor; Moechars, Dieder; Gijsen, Harrie; Trabanco, Andres A.
Journal of Medicinal Chemistry (2015), 58 (20), 8216-8235CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
1,4-Oxazines are presented, which show good in vitro inhibition in enzymic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and esp. P-glycoprotein efflux. This led to compds. which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, resp., in mouse and dog models. The amyloid lowering potential of these mols. makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.
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124
Scattolin, T.; Deckers, K.; Schoenebeck, F. Efficient synthesis of trifluoromethyl amines through a formal umpolung strategy from the bench-stable precursor (Me₄N)SCF₃. Angew. Chem., Int. Ed. 2017, 56, 221– 224, DOI: 10.1002/anie.201609480
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124
Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3
Scattolin, Thomas; Deckers, Kristina; Schoenebeck, Franziska
Angewandte Chemie, International Edition (2017), 56 (1), 221-224CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Reported herein is the one-pot synthesis of trifluoromethylated amines at room temp. using the bench-stable (Me4N)SCF3 reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF3 with the amine, giving quant. formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF3. The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug mols.
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125
Asahina, Y.; Araya, I.; Iwase, K.; Iinuma, F.; Hosaka, M.; Ishizaki, T. Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel N-1 substituent. J. Med. Chem. 2005, 48, 3443– 3446, DOI: 10.1021/jm040204g
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126
Schow, S. R.; Mackman, R. L.; Blum, C. L.; Brooks, E.; Horsma, A. G.; Joly, A.; Kerwar, S. S.; Lee, G.; Shiffman, D.; Nelson, M. G.; Wang, X.; Wick, M. M.; Zhang, X.; Lum, R. T. Synthesis and activity of 2,6,9-trisubstituted purines. Bioorg. Med. Chem. Lett. 1997, 7, 2697– 2702, DOI: 10.1016/S0960-894X(97)10076-2
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127
Miao, Z.; Zhu, L.; Dong, G.; Zhuang, C.; Wu, Y.; Wang, S.; Guo, Z.; Liu, Y.; Wu, S.; Zhu, S.; Fang, K.; Yao, J.; Li, J.; Sheng, C.; Zhang, W. A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors. J. Med. Chem. 2013, 56, 7902– 7910, DOI: 10.1021/jm400906z
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127
A New Strategy To Improve the Metabolic Stability of Lactone: Discovery of (20S,21S) 21-Fluorocamptothecins as Novel, Hydrolytically Stable Topoisomerase I Inhibitors
Miao, Zhenyuan; Zhu, Lingjian; Dong, Guoqiang; Zhuang, Chunlin; Wu, Yuelin; Wang, Shengzheng; Guo, Zizao; Liu, Yang; Wu, Shanchao; Zhu, Shiping; Fang, Kun; Yao, Jianzhong; Li, Jian; Sheng, Chunquan; Zhang, Wannian
Journal of Medicinal Chemistry (2013), 56 (20), 7902-7910CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Lactone is a common structural motif in biol. active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin deriv., (20S,21S)-7-Cyclohexyluorocamptothecin, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. The authors' results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone.
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128
Wipf, P.; Henninger, T. C.; Geib, S. J. Methyl- and (trifluoromethyl)alkene peptide isosteres: synthesis and evaluation of their potential as β-turn promoters and peptide mimetics. J. Org. Chem. 1998, 63, 6088– 6089, DOI: 10.1021/jo981057v
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128
Methyl- and (Trifluoromethyl)alkene Peptide Isosteres: Synthesis and Evaluation of Their Potential as β-Turn Promoters and Peptide Mimetics
Wipf, Peter; Henninger, Todd C.; Geib, Steven J.
Journal of Organic Chemistry (1998), 63 (18), 6088-6089CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Enantioselective synthetic approaches were devised for L-ala-D-Ala (or enantiomeric) dipeptide alkene isostere sequences that, for the first time, included the prepn. of a (trifluoromethyl)alkene isostere. An X-ray study established that methyl- and trifluoromethyl-substituted alkenes provide conformationally considerably more highly preorganized backbone-rigidified peptide mimetics than the parent disubstituted alkenes.
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129
(a) Urban, J. J.; Tillman, B. G.; Cronin, W. A. Fluoroolefins as peptide mimetics: a computational study of structure, charge distribution, hydration, and hydrogen bonding. J. Phys. Chem. A 2006, 110, 11120– 11129, DOI: 10.1021/jp062881n
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(b) Drouin, M.; Paquin, J.-F. Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres. Beilstein J. Org. Chem. 2017, 13, 2637– 2658
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129b
Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isostere
Drouin, Myriam; Paquin, Jean-Francois
Beilstein Journal of Organic Chemistry (2017), 13 (), 2637-2658CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
A review. Monofluoroalkenes are fluorinated motifs that can be used to replace amide bonds. In order to be incorporated into peptides, it is normally necessary to first synthesize a dipeptide where the amide bond has been replaced with a monofluoroalkene. In that context, this review will present the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isostere described since 2007. Some applications of those compds. will also be presented.
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(c) Drouin, M.; Hamel, J.-F.; Paquin, J.-F. Synthesis of monofluoroalkenes: a leap forward. Synthesis 2018, DOI: 10.1055/s-0036-1591867
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130
Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Chiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studies. Org. Biomol. Chem. 2007, 5, 1151– 1157, DOI: 10.1039/b701559c
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130
Chiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studies
Couve-Bonnaire, Samuel; Cahard, Dominique; Pannecoucke, Xavier
Organic & Biomolecular Chemistry (2007), 5 (8), 1151-1157CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
A review. The replacement of the amide bond in a peptide backbone is a promising strategy in peptidomimetic drug research. Over the various amide bond surrogates, the fluoroolefin moiety has been successfully developed as an effective mimic. Today, fluorine-contg. compds. account for a large proportion of new active mols. in life sciences. The synthesis of fluoroolefin peptide mimics is not a trivial task and innovative approaches often need to be addressed, in particular for the stereocontrol of the double bond configuration and the chiral centers adjacent to the fluoroalkene. These fluorinated peptidomimetics have been synthesized and evaluated as metabolically stable and/or conformationally constrained analogs of enzyme inhibitors, and as tools for probing the function, structure, and binding process of receptors.
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131
Nadon, J.-F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T. H.; Blais, V.; Guérin, B.; Gendron, L.; Dory, Y. L. Synthesis of Gly-ψ[(Z)CF═CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimetic. ACS Chem. Neurosci. 2017, 8, 40– 49, DOI: 10.1021/acschemneuro.6b00163
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131
Synthesis of Gly-ψ[(Z)CF=CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimetic
Nadon, Jean-Francois; Rochon, Kristina; Grastilleur, Sebastien; Langlois, Guillaume; Dao, Thi Thanh Ha; Blais, Veronique; Guerin, Brigitte; Gendron, Louis; Dory, Yves L.
ACS Chemical Neuroscience (2017), 8 (1), 40-49CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
A new Leu-enkephalin peptidomimetic designed to explore the hydrogen bond acceptor ability of the third peptide bond has been prepd. and studied. This new analog is produced by replacing the third amide of Leu-enkephalin with a fluoroalkene. An efficient and innovative synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(Z)CF=CH]-Phe-OH is described. The key step involves the alkylation of a tin dienolate from the less hindered face of its chiral sulfonamide auxiliary derived from camphor. Once its synthesis was complete, its incorporation into the peptidomimetic sequence was achieved on a solid support with chlorotrityl resin following the Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) strategy. The peptidomimetic was characterized using competition binding with [125I]-deltorphin I on membrane exts. of HEK293 cells expressing the mouse delta opioid receptor (DOPr) and based on its abilities to inhibit the elec. induced contractions of the mouse vas deferens and to activate the ERK1/2 signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous observations, our findings strongly suggest that the third amide bond of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr. Consequently, this amide bond can be successfully replaced by an ester, a thioamide, or a fluoroalkene without greatly impacting the binding or biol. activity of the corresponding analogs. The lipophilicity (LogD7.4) of the active analog was also measured. It appears that fluoroalkenes are almost as efficient at increasing the lipophilicity as normal alkenes.
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Karad, S. N.; Pal, M.; Crowley, R. S.; Prisinzano, T. E.; Altman, R. A. Synthesis and opioid activity of Tyr¹-Ψ(Z)CF═CH]-Gly² and Tyr¹-Ψ(S)/(R)CF₃CH-NH]-Gly² Leu enkephalin fluorinated peptidomimetics. ChemMedChem 2017, 12, 571– 576, DOI: 10.1002/cmdc.201700103
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133
Rogers, M. T. The electric moments of some unsaturated aldehydes, ethers and halogen compounds. J. Am. Chem. Soc. 1947, 69, 1243– 1246, DOI: 10.1021/ja01198a003
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134
(a) Kobayakawa, T.; Narumi, T.; Tamamura, H. Remote stereoinduction in the organocuprate-mediated allylic alkylation of allylic gem-dichlorides: highly diastereoselective synthesis of (Z)-chloroalkene dipeptide isosteres. Org. Lett. 2015, 17, 2302– 2305, DOI: 10.1021/acs.orglett.5b00611
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(b) Waelchli, R.; Gamse, R.; Bauer, W.; Lier, E.; Feyen, J. H. M. Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogues of hPTH(1–36) fragment. Bioorg. Med. Chem. Lett. 1996, 6, 1151– 1156, DOI: 10.1016/0960-894X(96)00188-6
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134b
Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogs of hPTH(1-36) fragment
Waelchli, Rudolf; Gamse, Rainer; Bauer, Wilfried; Meigel, Harald; Lier, Edouard; Feyen, Jean H. M.
Bioorganic & Medicinal Chemistry Letters (1996), 6 (10), 1151-1156CODEN: BMCLE8; ISSN:0960-894X. (Elsevier)
A series of human parathyroid hormone (1-36) [hPTH(1-36)] analogs were prepd. to study the role of the first peptide bond between residues Ser1-Val2. Some of these analogs were found to show high affinity binding in intact opossum kidney (OK-1) cells and were very active in their ability to stimulate adenylate cyclase prodn. in intact OK-1 cells, rat UMR-106-06 osteosarcoman cells and SaOS-2 human osteosarcoma cells.
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(c) Kobayakawa, T.; Matsuzaki, Y.; Hozumi, K.; Nomura, W.; Nomizu, M.; Tamamura, H. Synthesis of a Chloroalkene dipeptide isostere-containing peptidomimetic and its biological application. ACS Med. Chem. Lett. 2018, 9, 6– 10, DOI: 10.1021/acsmedchemlett.7b00234
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134c
Synthesis of a chloroalkene dipeptide isostere-containing peptidomimetic and its biological application
Kobayakawa, Takuya; Matsuzaki, Yudai; Hozumi, Kentaro; Nomura, Wataru; Nomizu, Motoyoshi; Tamamura, Hirokazu
ACS Medicinal Chemistry Letters (2018), 9 (1), 6-10CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
The first rapid and efficient chem. synthesis of a cyclic Arg-Gly-Asp (RGD) peptide contg. a chloroalkene dipeptide isostere (CADI) is reported. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI was obtained utilizing diastereoselective allylic alkylation as a key reaction. This CADI was also transformed into an N-Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) protected CADI in a few steps. The CADI was used in Fmoc-based solid-phase peptide synthesis. The first synthesis of a CADI-contg. cyclic RGD peptide was successful, and the synthesized CADI-contg. peptidomimetic was found to be a more potent inhibitor against integrin-mediated cell attachment than the parent cyclic peptide.
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135
Edmondson, S. D.; Wei, L.; Xu, J.; Shang, J.; Xu, S.; Pang, J.; Chaudhary, A.; Dean, D. C.; He, H.; Leiting, B.; Lyons, K. A.; Patel, R. A.; Patel, S. B.; Scapin, G.; Wu, J. K.; Beconi, M. G.; Thornberry, N. A.; Weber, A. E. Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 2409– 2413, DOI: 10.1016/j.bmcl.2008.02.050
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135
Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors
Edmondson, Scott D.; Wei, Lan; Xu, Jinyou; Shang, Jackie; Xu, Shiyao; Pang, Jianmei; Chaudhary, Ashok; Dean, Dennis C.; He, Huaibing; Leiting, Barbara; Lyons, Kathryn A.; Patel, Reshma A.; Patel, Sangita B.; Scapin, Giovanna; Wu, Joseph K.; Beconi, Maria G.; Thornberry, Nancy A.; Weber, Ann E.
Bioorganic & Medicinal Chemistry Letters (2008), 18 (7), 2409-2413CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
The synthesis, selectivity, rat pharmacokinetic profile, and drug metab. profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
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136
(a) Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics. Bioorg. Med. Chem. Lett. 2012, 22, 2938– 2942, DOI: 10.1016/j.bmcl.2012.02.051
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136a
Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics
Chang, Wonsuk; Mosley, Ralph T.; Bansal, Shalini; Keilman, Meg; Lam, Angela M.; Furman, Phillip A.; Otto, Michael J.; Sofia, Michael J.
Bioorganic & Medicinal Chemistry Letters (2012), 22 (8), 2938-2942CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-mol. hydrogen bonds were a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin contg. inhibitor exhibited picomolar activity (EC50 = 79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
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(b) Belema, M.; Lopez, O. D.; Bender, J. A.; Romine, J. L.; St. Laurent, D. R.; Langley, D. R.; Lemm, J. A.; O’Boyle, D. R., II; Sun, J.-H.; Wang, C.; Fridell, R. A.; Meanwell, N. A. The discovery and development of hepatitis C virus NS5A replication complex inhibitors. J. Med. Chem. 2014, 57, 1643– 1672, DOI: 10.1021/jm401793m
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136b
Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors
Belema, Makonen; Lopez, Omar D.; Bender, John A.; Romine, Jeffrey L.; St. Laurent, Denis R.; Langley, David R.; Lemm, Julie A.; O'Boyle, Donald R., II; Sun, Jin-Hua; Wang, Chunfu; Fridell, Robert A.; Meanwell, Nicholas A.
Journal of Medicinal Chemistry (2014), 57 (5), 1643-1672CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chem. studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compds. currently in clin. trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogs that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clin. trials with HCV NS5A RCIs.
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137
Hollenstein, M.; Leumann, C. J. Fluorinated olefinic peptide nucleic acid: synthesis and pairing properties with complementary DNA. J. Org. Chem. 2005, 70, 3205– 3217, DOI: 10.1021/jo047753e
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137
Fluorinated Olefinic Peptide Nucleic Acid: Synthesis and Pairing Properties with Complementary DNA
Hollenstein, Marcel; Leumann, Christian J.
Journal of Organic Chemistry (2005), 70 (8), 3205-3217CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The fluorinated olefinic peptide nucleic acid (F-OPA) system was designed as a peptide nucleic acid (PNA) analog in which the base carrying amide moiety was replaced by an isostructural and isoelectrostatic fluorinated C-C double bond, locking the nucleobases in one of the two possible rotameric forms. By comparison of the base-pairing properties of this analog with its nonfluorinated analog OPA and PNA, the authors attempted a closer understanding of the role of this amide function in complementary DNA recognition. Here, the synthesis of the F-OPA monomer building blocks contg. the nucleobases A, T, and G according to the MMTr/Acyl protecting group scheme is presented. Key steps are a selective desymmetrization of the double bond in the monomer precursor via lactonization as well as a highly regioselective Mitsunobu reaction for the introduction of the bases. PNA decamers contg. single F-OPA mutations and fully modified F-OPA decamers and pentadecamers contg. the bases A and T were synthesized by solid-phase peptide chem., and their hybridization properties with complementary parallel and antiparallel DNA were assessed by UV melting curves and CD spectroscopic methods. The stability of the duplexes formed by the decamers contg. single (Z)-F-OPA modifications with parallel and antiparallel DNA was found to be strongly dependent on their position in the sequence with Tm values ranging from +2.4 to -8.1°/modification as compared to PNA. Fully modified F-OPA decamers and pentadecamers were found to form parallel duplexes with complementary DNA with reduced stability compared to PNA or OPA. An asym. F-OPA pentadecamer was found to form a stable self-complex (Tm ∼ 65°) of unknown structure. The generally reduced affinity to DNA may therefore be due to an increased propensity for self-aggregation.
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138
(a) Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.; Hayes, M. J.; Jones, D. E.; Neumann, W. L.; Wood, R. S.; Lachance, R. M.; Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. J. Med. Chem. 2003, 46, 4050– 4062, DOI: 10.1021/jm030131l
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(b) Parlow, J. J.; Stevens, A. M.; Stegeman, R. A.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Synthesis and crystal structures of substituted benzenes and benzoquinones as tissue factor VIIa inhibitors. J. Med. Chem. 2003, 46, 4297– 4312, DOI: 10.1021/jm030233b
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138b
Synthesis and Crystal Structures of Substituted Benzenes and Benzoquinones as Tissue Factor VIIa Inhibitors
Parlow, John J.; Stevens, Anna M.; Stegeman, Roderick A.; Stallings, William C.; Kurumbail, Ravi G.; South, Michael S.
Journal of Medicinal Chemistry (2003), 46 (20), 4297-4312CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Several multistep syntheses of substituted benzenes are reported. The benzene analogs were designed such that their substitution pattern would occupy and interact with the S1, S2, and S3 pockets of the tissue Factor VIIa enzyme. A variety of chem. transformations including nucleophilic addns., reductive aminations, Stille couplings, and polymer-assisted soln.-phase (PASP) techniques were used to prep. key intermediates and final products. The initial analogs identified some weakly active compds. which ultimately led to a 340 nM (IC50) tissue Factor VIIa inhibitor with selectivity over other related enzymes. The structure-activity relationship of these inhibitors and the synthetic progression from the discovery of the lead compd. to the development of potent analogs will be discussed. The X-ray crystal structures of 3'-amino-N-[[4-(aminoiminomethyl)phenyl]methyl]-3-fluoro-4-[(1-methylethyl)amino]-[1,1'-biphenyl]-2-acetamide and N-[[4-(aminoiminomethyl)phenyl]methyl]-5-[(1-methylethyl)amino]-3,6-dioxo-2-phenyl-1,4-cyclohexadiene-1-acetamide inhibitors complexed with the TF/VIIa enzyme will also be described. Other compds. thus prepd. and screened included N-[[4-(aminoiminomethyl)phenyl]methyl]-3-hydroxy-4-[(1-methylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-3-hydroxy-4-[(2-phenylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-3-fluoro-4-[(2-phenylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-2,6-difluoro-3-[[(phenylmethyl)sulfonyl]amino]benzeneacetamide.
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(c) Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; South, M. S. Synthesis and X-ray crystal structures of substituted fluorobenzene and benzoquinone inhibitors of the tissue factor VIIa complex. Bioorg. Med. Chem. Lett. 2003, 13, 3721– 3725, DOI: 10.1016/j.bmcl.2003.08.002
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(d) Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; South, M. S. Design, synthesis, and crystal structure of selective 2-pyridone tissue factor VIIa inhibitors. J. Med. Chem. 2003, 46, 4696– 4701, DOI: 10.1021/jm0301686
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138d
Design, Synthesis, and Crystal Structure of Selective 2-Pyridone Tissue Factor VIIa Inhibitors
Parlow, John J.; Kurumbail, Ravi G.; Stegeman, Roderick A.; Stevens, Anna M.; Stallings, William C.; South, Michael S.
Journal of Medicinal Chemistry (2003), 46 (22), 4696-4701CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Targeted 2-pyridones were selected as tissue factor VIIa inhibitors and prepd. from 2,6-dibromopyridine via a multistep synthesis. A variety of chem. transformations, including regioselective nucleophilic addn., selective nitrogen alkylation, and a Suzuki coupling, afforded the targeted tissue factor VIIa inhibitors. The pyridone core was selected as a replacement for the pyrazinone core of noncovalent tissue Factor VIIa inhibitors and designed such that their substitution pattern would occupy and interact with the S1, S2, and S3 pockets of the tissue factor VIIa enzyme. These compds. were tested in several serine protease enzyme assays involved in the coagulation cascade exhibiting modest activity on tissue factor VIIa with excellent selectivity over thrombin and Factor Xa. Finally, an X-ray crystal structure of one inhibitor bound to tissue factor VIIa was obtained and will be described. Compds. thus prepd. and tested were 3-amino-5-[1-[2-[[[4-(aminoiminomethyl)phenyl]methyl]amino]-2-oxoethyl]-1,6-dihydro-5-[(1-methylethyl)amino]-6-oxo-2-pyridinyl]benzoic acid and N-[[4-(aminoiminomethyl)phenyl]methyl]-6-(3,5-diaminophenyl)-3-[(1-methylethyl)amino]-2-oxo-1(2H)-pyridineacetamide.
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139
(a) Lee, L.; Kreutter, K. D.; Pan, W.; Crysler, C.; Spurlino, J.; Player, M. R.; Tomczuk, B.; Lu, T. 2-(2-Chloro-6-fluorophenyl)-acetamides as potent thrombin inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 6266– 6269, DOI: 10.1016/j.bmcl.2007.09.013
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(b) Kreutter, K. D.; Lu, T.; Lee, L.; Giardino, E. C.; Patel, S.; Huang, H.; Xu, G.; Fitzgerald, M.; Haertlein, B. J.; Mohan, V.; Crysler, C.; Eisennagel, S.; Dasgupta, M.; McMillan, M.; Spurlino, J. C.; Huebert, N. D.; Maryanoff, B. E.; Tomczuk, B. E.; Damiano, B. P.; Player, M. R. Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif. Bioorg. Med. Chem. Lett. 2008, 18, 2865– 2870, DOI: 10.1016/j.bmcl.2008.03.087
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(c) Nantermet, P. G.; Burgey, C. S.; Robinson, K. A.; Pellicore, J. M.; Newton, C. L.; Deng, J. M.; Selnick, H. G.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Miller-Stein, C.; White, R. B.; Wong, B.; McMasters, D. R.; Wallace, A. A.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P.; Lyle, T. A. P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold. Bioorg. Med. Chem. Lett. 2005, 15, 2771– 2775, DOI: 10.1016/j.bmcl.2005.03.110
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(d) Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Sanderson, P. E. J.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P. D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J. C.; Stranieri, M. T.; Holahan, M. A.; Sitko, G. R.; Cook, J. J.; McMasters, D. R.; McDonough, C. M.; Sanders, W. M.; Wallace, A. A.; Clayton, F. C.; Bohn, D.; Leonard, Y. M.; Detwiler, T. J., Jr.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P. Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. J. Med. Chem. 2003, 46, 461– 473, DOI: 10.1021/jm020311f
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140
(a) Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. The pKBHX database: toward a better understanding of hydrogen-bond basicity for medicinal chemists. J. Med. Chem. 2009, 52, 4073– 4086, DOI: 10.1021/jm801331y
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140a
The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal Chemists
Laurence, Christian; Brameld, Ken A.; Graton, Jerome; Le Questel, Jean-Yves; Renault, Eric
Journal of Medicinal Chemistry (2009), 52 (14), 4073-4086CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. The pKBHX database is presented, which corresponds to three main fields of data: hydrogen bond donor identification, thermodn. data and spectroscopic data. The pKBHX scale of hydrogen donor basicity differs considerable from the pKBH+ scale of proton transfer basicity. The hydrogen bond basicities of functional groups relevant to medicinal chem. and drug design is reviewed.
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(b) Kenny, P. W.; Montanari, C. A.; Prokopczyk, I. M.; Ribeiro, J. F.; Sartori, G. R. Hydrogen bond basicity prediction for medicinal chemistry design. J. Med. Chem. 2016, 59, 4278– 4288, DOI: 10.1021/acs.jmedchem.5b01946
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140b
Hydrogen Bond Basicity Prediction for Medicinal Chemistry Design
Kenny, Peter W.; Montanari, Carlos A.; Prokopczyk, Igor M.; Ribeiro, Jean F. R.; Sartori, Geraldo Rodrigues
Journal of Medicinal Chemistry (2016), 59 (9), 4278-4288CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Hydrogen bonding is discussed in the context of medicinal chem. design. Minimized mol. electrostatic potential (Vmin) is shown to be an effective predictor of hydrogen bond basicity (pKBHX), and predictive models are presented for a no. of hydrogen bond acceptor types relevant to medicinal chem. The problems posed by the presence of nonequivalent hydrogen bond acceptor sites in mol. structures are addressed by using nonlinear regression to fit measured pKBHX to calcd. Vmin. Predictions are made for hydrogen bond basicity of fluorine in situations where relevant exptl. measurements are not available. It is shown how predicted pKBHX can be used to provide insight into the nature of bioisosterism and to profile heterocycles. Examples of pKBHX prediction for mol. structures with multiple, nonequivalent hydrogen bond acceptors are presented.
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(c) Pierce, A. C.; Sandretto, K. L.; Bemis, G. W. Kinase inhibitors and the case for CH···O hydrogen bonds in protein-ligand binding. Proteins: Struct., Funct., Genet. 2002, 49, 567– 576, DOI: 10.1002/prot.10259
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140c
Kinase inhibitors and the case for CH···O hydrogen bonds in protein-ligand binding
Pierce, Albert C.; Sandretto, Kathryn L.; Bemis, Guy W.
Proteins: Structure, Function, and Genetics (2002), 49 (4), 567-576CODEN: PSFGEY; ISSN:0887-3585. (Wiley-Liss, Inc.)
Although the hydrogen bond is known to be an important mediator of intermol. interactions, there has yet to be an anal. of the role of CH···O hydrogen bonds in protein-ligand complexes. In this work, we present evidence for such nonstandard hydrogen bonds from a survey of arom. ligands in 184 kinase crystal structures and 358 high-resoln. structures from the Protein Data Bank. CH groups adjacent to the pos. charged nitrogen of nicotinamide exhibit geometric preferences strongly suggestive of hydrogen bonding interactions, as do heterocyclic CH groups in kinase ligands, while other arom. CH groups do not exhibit these characteristics. Ab initio calcns. reveal a considerable range of CH···O hydrogen bonding potentials among different arom. ring systems, with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. These results provide compelling evidence for the existence of CH···O hydrogen bonds in protein-ligand interactions, as well as information on the relative strength of various arom. CH donors. Such knowledge will be of considerable value in protein modeling, ligand design, and structure-activity anal.
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141
Anilkumar, G. N.; Lesburg, C. A.; Selyutin, O.; Rosenblum, S. B.; Zeng, Q.; Jiang, Y.; Chan, T.-Y.; Pu, H.; Vaccaro, H.; Wang, L.; Bennett, F.; Chen, K. X.; Duca, J.; Gavalas, S.; Huang, Y.; Pinto, P.; Sannigrahi, M.; Velazquez, F.; Venkatraman, S.; Vibulbhan, B.; Agrawal, S.; Butkiewicz, N.; Feld, B.; Ferrari, E.; He, Z.; Jiang, C.-k.; Palermo, R. E.; Mcmonagle, P.; Huang, H.-C.; Shih, N.-Y.; Njoroge, G.; Kozlowski, J. A. I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles. Bioorg. Med. Chem. Lett. 2011, 21, 5336– 5341, DOI: 10.1016/j.bmcl.2011.07.021
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141
I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocycles
Anilkumar, Gopinadhan N.; Lesburg, Charles A.; Selyutin, Oleg; Rosenblum, Stuart B.; Zeng, Qingbei; Jiang, Yueheng; Chan, Tin-Yau; Pu, Haiyan; Vaccaro, Henry; Wang, Li; Bennett, Frank; Chen, Kevin X.; Duca, Jose; Gavalas, Stephen; Huang, Yuhua; Pinto, Patrick; Sannigrahi, Mousumi; Velazquez, Francisco; Venkatraman, Srikanth; Vibulbhan, Bancha; Agrawal, Sony; Butkiewicz, Nancy; Feld, Boris; Ferrari, Eric; He, Zhiqing; Jiang, Chuan-kui; Palermo, Robert E.; McMonagle, Patricia; Huang, H.-C.; Shih, Neng-Yang; Njoroge, George; Kozlowski, Joseph A.
Bioorganic & Medicinal Chemistry Letters (2011), 21 (18), 5336-5341CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead I (NS5B IC50 = 0.9 μM, replicon EC50 >100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in lead carboxyindoles II (NS5B IC50 = 0.032 μM, replicon EC50 = 1.4 μM) and III (NS5B IC50 = 0.017 μM, replicon EC50 = 0.3 μM) with improved enzyme and replicon activity.
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142
Adams, M. E.; Wallace, M. B.; Kanouni, T.; Scorah, N.; O’Connell, S. M.; Miyake, H.; Shi, L.; Halkowycz, P.; Zhang, L.; Dong, Q. Design and synthesis of orally available MEK inhibitors with potent in vivo antitumor efficacy. Bioorg. Med. Chem. Lett. 2012, 22, 2411– 2414, DOI: 10.1016/j.bmcl.2012.02.026
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143
(a) Isshiki, Y.; Kohchi, Y.; Iikura, H.; Matsubara, Y.; Asoh, K.; Murata, T.; Kohchi, M.; Mizuguchi, E.; Tsujii, S.; Hattori, K.; Miura, T.; Yoshimura, Y.; Aida, S.; Miwa, M.; Saitoh, R.; Murao, N.; Okabe, H.; Belunis, C.; Janson, C.; Lukacs, C.; Schück, V.; Shimma, N. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg. Med. Chem. Lett. 2011, 21, 1795– 1801, DOI: 10.1016/j.bmcl.2011.01.062
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(b) Leijen, S.; Middleton, M. R.; Tresca, P.; Kraeber-Bodéré, F.; Dieras, V.; Scheulen, M. E.; Gupta, A.; Lopez-Valverde, V.; Xu, Z. X.; Rueger, R.; Tessier, J. J.; Shochat, E.; Blotner, S.; Naegelen, V. M.; Schellens, J. H.; Eberhardt, W. E. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin. Cancer Res. 2012, 18, 4794– 4805, DOI: 10.1158/1078-0432.CCR-12-0868
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143b
Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors
Leijen, Suzanne; Middleton, Mark R.; Tresca, Patricia; Kraeber-Bodere, Francoise; Dieras, Veronique; Scheulen, Max E.; Gupta, Avinash; Lopez-Valverde, Vanesa; Xu, Zhi-Xin; Rueger, Ruediger; Tessier, Jean J. L.; Shochat, Eliezer; Blotner, Steve; Naegelen, Valerie Meresse; Schellens, Jan H. M.; Eberhardt, Wilfried Ernst Erich
Clinical Cancer Research (2012), 18 (17), 4794-4805CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
Purpose: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its max. tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-wk cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. Results: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approx. 4 h. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC50). Of the patients evaluable for response, clin. benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a redn. in fluorodeoxyglucose uptake by positron emission tomog. between baseline and day 15. Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. Clin Cancer Res; 18(17); 4794-805. ©2012 AACR.
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144
Ohren, J. F.; Chen, H.; Pavlovsky, A.; Whitehead, C.; Zhang, E.; Kuffa, P.; Yan, C.; McConnell, P.; Spessard, C.; Banotai, C.; Mueller, W. T.; Delaney, A.; Omer, C.; Sebolt-Leopold, J.; Dudley, D. T.; Leung, I. K.; Flamme, C.; Warmus, J.; Kaufman, M.; Barrett, S.; Tecle, H.; Hasemann, C. A. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 2004, 11, 1192– 1197, DOI: 10.1038/nsmb859
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144
Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition
Ohren, Jeffrey F.; Chen, Huifen; Pavlovsky, Alexander; Whitehead, Christopher; Zhang, Erli; Kuffa, Peter; Yan, Chunhong; McConnell, Patrick; Spessard, Cindy; Banotai, Craig; Mueller, W. Thomas; Delaney, Amy; Omer, Charles; Sebolt-Leopold, Judith; Dudley, David T.; Leung, Iris K.; Flamme, Cathlin; Warmus, Joseph; Kaufman, Michael; Barrett, Stephen; Tecle, Haile; Hasemann, Charles A.
Nature Structural & Molecular Biology (2004), 11 (12), 1192-1197CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
MEK1 and MEK2 kinases are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK MAP kinase (MAPK) signaling pathway. Approx. 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here, the authors present the x-ray crystal structures of human MEK1 and MEK2 kinases, each detd. as a ternary complex with MgATP and an inhibitor to a resoln. of 2.4 and 3.2 Å, resp. The structures revealed that MEK1 and MEK2 each had a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitors induced several conformational changes in the unphosphorylated MEK1 and MEK2 kinases that locked them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.
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145
Kong, J. W.; Hamann, L. G.; Ruppar, D. A.; Edwards, J. P.; Marschke, K. B.; Jones, T. K. Effects of isosteric pyridone replacements in androgen receptor antagonists based on 1,2-dihydro- and 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinolones. Bioorg. Med. Chem. Lett. 2000, 10, 411– 414, DOI: 10.1016/S0960-894X(00)00010-X
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146
Qiu, J.; Stevenson, S. H.; O'Beirne, M. J.; Silverman, R. B. 2,6-Difluorophenol as a bioisostere of a carboxylic acid: bioisosteric analogues of γ-aminobutyric acid. J. Med. Chem. 1999, 42, 329– 332, DOI: 10.1021/jm980435l
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147
(a) Nicolaou, I.; Zika, C.; Demopoulos, V. J. [1-(3,5-Difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone as a bioisostere of a carboxylic acid aldose reductase inhibitor. J. Med. Chem. 2004, 47, 2706– 2709, DOI: 10.1021/jm031060t
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(b) Alexiou, P.; Demopoulos, V. J. A diverse series of substituted benzenesulfonamides as aldose reductase inhibitors with antioxidant activity: design, synthesis, and in vitro activity. J. Med. Chem. 2010, 53, 7756– 7766, DOI: 10.1021/jm101008m
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147b
A Diverse Series of Substituted Benzenesulfonamides as Aldose Reductase Inhibitors with Antioxidant Activity: Design, Synthesis, and in Vitro Activity
Alexiou, Polyxeni; Demopoulos, Vassilis J.
Journal of Medicinal Chemistry (2010), 53 (21), 7756-7766CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Based on bioisosteric principles, 2,6-difluorophenol and tetrazole, methylsulfonylamide, and isoxazolidin-3-one phenylsulfonamide derivs. were synthesized and tested in vitro in protocols primarily related to the long-term diabetic complications. Most of the compds. were found as aldose reductase inhibitors (ARIs) at IC50 < 100 μM, while the introduction of the 4-bromo-2-fluorobenzyl group in a phenylsulfonamidodifluorophenol structure resulted in I, presenting a submicromolar inhibitory profile. However, the derivs. of tetrazole, methylsulfonylamine, and the (R)-enantiomer of isoxazolidin-3-one did not exhibit appreciable aldose reductase inhibitors (ARI) activity. The selectivity of the active ARIs is also discussed. Furthermore, the synthesized compds. exhibit potent antioxidant potential (homogeneous and heterogeneous systems).
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(c) Kotsampasakou, E.; Demopoulos, V. J. Synthesis of derivatives of the keto-pyrrolyl-difluorophenol scaffold: some structural aspects for aldose reductase inhibitory activity and selectivity. Bioorg. Med. Chem. 2013, 21, 869– 873, DOI: 10.1016/j.bmc.2012.12.015
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148
(a) Burkhart, J. P.; Weintraub, P. M.; Gates, C. A.; Resvick, R. J.; Vaz, R. J.; Friedrich, D.; Angelastro, M. R.; Bey, P.; Peet, N. P. Novel steroidal vinyl fluorides as inhibitors of steroid C₁₇₍₂₀₎ lyase. Bioorg. Med. Chem. 2002, 10, 929– 934, DOI: 10.1016/S0968-0896(01)00354-6
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(b) Corina, D. L.; Miller, S. L.; Wright, J. N.; Akhtar, M. The mechanism of cytochrome P-450 dependent C-C bond cleavage: studies on 17α-hydroxylase-I7,20-lyase. J. Chem. Soc., Chem. Commun. 1991, 782– 783, DOI: 10.1039/C39910000782
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Li, X.; Singh, S. M.; Luu-The, V.; Côté, J.; Laplante, S.; Labrie, F. Vinyl fluoride as a mimic of the ’intermediate’ enol form in the 5α-reductase transformation: synthesis and in vitro activity of (N-1′, 1′-dimethylethyl)-3-haloandrost-3,5-diene-17β-carboxamides. Bioorg. Med. Chem. 1996, 4, 55– 60, DOI: 10.1016/0968-0896(95)00160-3
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Pirrung, M. C.; Ha, H.-J.; Holmes, C. P. Purification and inhibition of spinach αβ,-dihydroxyacid dehydratase. J. Org. Chem. 1989, 54, 1543– 1548, DOI: 10.1021/jo00268a014
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Dixon, D. A.; Fukunaga, T.; Smart, B. E. Geometries and energies of the fluoroethylenes. J. Am. Chem. Soc. 1986, 108, 1585– 1588, DOI: 10.1021/ja00267a031
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152
Leriche, C.; He, X.; Chang, C.-w. T.; Liu, H.-w. Reversal of the apparent regiospecificity of NAD(P)H-dependent hydride transfer: the properties of the difluoromethylene group, a carbonyl mimic. J. Am. Chem. Soc. 2003, 125, 6348– 6349, DOI: 10.1021/ja021487+
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152
Reversal of the Apparent Regiospecificity of NAD(P)H-Dependent Hydride Transfer: The Properties of the Difluoromethylene Group, A Carbonyl Mimic
Leriche, Caroline; He, Xuemei; Chang, Cheng-wei T.; Liu, Hung-wen
Journal of the American Chemical Society (2003), 125 (21), 6348-6349CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The hallmarks of pyridine nucleotide-dependent dehydrogenase reactions are the stereo- and regiospecific hydride transfer between the nicotinamide coenzyme and the corresponding substrate. When the hydride is delivered from NAD(P)H to reduce the keto-substrate, the site of attack is always at the carbonyl carbon. However, the apparent regioselectivity of the hydride transfer is reversed when difluoromethylene is used as a carbonyl mimic in the NADH-dependent enzyme, TDP-L-rhamnose synthase, which catalyzes the conversion of TDP-6-deoxy-L-lyxo-4-hexulose to TDP-L-rhamnose. The obsd. reversed regioselectivity can be explained by two mechanisms. One involves the formation of a carbene intermediate followed by a rearrangement involving 1,2-H shift. This mechanistic proposal is theor. sound and would represent a rare example implicating the intermediacy of a carbene species in an enzyme reaction. However, our results are also consistent with a second mechanism in which the hydride addn. to the difluoromethylene moiety occurs at the difluorinated end, opposite from the site predicted on the basis of the redn. of a normal keto functional group. Such a regioselectivity is well precedented in chem. models because nucleophilic addn. to fluoroalkenes prefers a route in which the no. of fluorines β to the electron-rich carbon in the transition state is maximized. In this mechanism, the difluoromethylene group may be regarded as a carbonyl mimic with reversed polarity in enzyme catalysis. While further expts. are needed to discriminate between these mechanistic possibilities, the results reported here suggest that the apparent regioselectivity of hydride transfer in a pyridine nucleotide-dependent enzyme can be changed by altering the electrochem. properties of the reaction center.
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153
Bickelhaupt, F. M.; Hermann, H. L.; Boche, G. α-Stabilization of carbanions: fluorine is more effective than the heavier halogens. Angew. Chem., Int. Ed. 2006, 45, 823– 826, DOI: 10.1002/anie.200501633
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154
(a) Bégué, J.-P.; Bonnet-Delpon, D. Fluoroartemisinins: metabolically more stable antimalarial artemisinin derivatives. ChemMedChem 2007, 2, 608– 624, DOI: 10.1002/cmdc.200600156
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154a
Fluoroartemisinins: metabolically more stable antimalarial artemisinin derivatives
Begue, Jean-Pierre; Bonnet-Delpon, Daniele
ChemMedChem (2007), 2 (5), 608-624CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This report is an overview on the design, prepn., and evaluation of metabolically stable artemisinins, using fluorine substitution. The chem. challenges encountered for the incorporation of fluorine-contg. elements and the prepn. of a large range of 10-trifluoromethyl artemisinin derivs. are detailed. Impact of the fluorine substitution on the antimalarial activity is also highlighted. Preclin. data of lead compds., and evidence for their strong and prolonged antimalarial activity are presented.
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(b) Magueur, G.; Crousse, B.; Ourévitch, M.; Bonnet-Delpon, D.; Bégué, J.-P. Fluoro-artemisinins: when a gem-difluoroethylene replaces a carbonyl group. J. Fluorine Chem. 2006, 127, 637– 642, DOI: 10.1016/j.jfluchem.2005.12.013
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154b
Fluoro-artemisinins: When a gem-difluoroethylene replaces a carbonyl group
Magueur, Guillaume; Crousse, Benoit; Ourevitch, Michele; Bonnet-Delpon, Daniele; Begue, Jean-Pierre
Journal of Fluorine Chemistry (2006), 127 (4-5), 637-642CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
Exo-gem-difluoromethylene-artemisinin (I) has been designed to mimic artemisinin. The classical Wittig olefination reaction applied to artemisinin failed. An alternative reaction involving the generation of an α-CF3 carbanion, from the corresponding bromide, allowed the access to the target compd. I, and could also be applied to the sugar series. The replacement of the carbonyl function by a difluoroethylene moiety resulted in a better antimalarial activity.
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155
(a) Tu, Y. Artemisinin- a gift from traditional Chinese medicine to the world (Nobel lecture). Angew. Chem., Int. Ed. 2016, 55, 10210– 10226, DOI: 10.1002/anie.201601967
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(b) Ashley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, C.; Runcharoen, R.; Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan, R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.; Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi, P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.; Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.; Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.; Tracking Resistance to Artemisinin Collaboration Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 2014, 371, 411– 423, DOI: 10.1056/NEJMoa1314981
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155b
Spread of artemisinin resistance in Plasmodium falciparum malaria
Ashley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, C.; Runcharoen, R.; Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan, R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.; Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi, P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.; Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.; Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.
New England Journal of Medicine (2014), 371 (5), 411-423, 13 pp.CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
Background: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geog. extent of resistance is essential for planning containment and elimination strategies. Methods: Between May 2011 and Apr. 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kg of body wt. per day or 4 mg per kg, for 3 days, followed by a std. 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 h, and the parasite clearance half-lives were detd. Results: The median parasite clearance half-lives ranged from 1.9 h in the Democratic Republic of Congo to 7.0 h at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 h), strongly assocd. with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from Southern Vietnam to central Myanmar. The incidence of pre-treatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In Western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was assocd. with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. Conclusions: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is assocd. with mutations in kelch13. Prolonged courses of artemisinin- based combination therapies are currently efficacious in areas where std. 3-day treatments are failing. (Funded by the U.K. Department of International Development and others).
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156
(a) Dubowchik, G. M.; Vrudhula, V. M.; Dasgupta, B.; Ditta, J.; Chen, T.; Sheriff, S.; Sipman, K.; Witmer, M.; Tredup, J.; Vyas, D. M.; Verdoorn, T. A.; Bollini, S.; Vinitsky, A. 2-Aryl-2,2-difluoroacetamide FKBP12 ligands: synthesis and X-ray structural studies. Org. Lett. 2001, 3, 3987– 3990, DOI: 10.1021/ol0166909
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156a
2-Aryl-2,2-difluoroacetamide FKBP12 Ligands: Synthesis and X-ray Structural Studies
Dubowchik, Gene M.; Vrudhula, Vivekananda M.; Dasgupta, Bireshwar; Ditta, Jonathan; Chen, Ti; Sheriff, Steven; Sipman, Karin; Witmer, Mark; Tredup, Jeffrey; Vyas, Dolatrai M.; Verdoorn, Todd A.; Bollini, Sagarika; Vinitsky, Alexander
Organic Letters (2001), 3 (25), 3987-3990CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
2-Aryl-2,2-difluoroacetamido derivs. of proline and pipecolate esters I (X = F2, O, H2; Y = N, CH) and II (p = 1, 2; n = 2, 3; m = 0-3) are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 Ph ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.
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(b) Bollini, S.; Herbst, J. J.; Gaughan, G. T.; Verdoorn, T. A.; Ditta, J.; Dubowchik, G. M.; Vinitsky, A. High-throughput fluorescence polarization method for identification of FKBP12 ligands. J. Biomol. Screening 2002, 7, 526– 530, DOI: 10.1177/1087057102238626
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156b
High-throughput fluorescence polarization method for identification of FKBP12 ligands
Bollini, S.; Herbst, J. J.; Gaughan, G. T.; Verdoorn, T. A.; Ditta, J.; Dubowchik, G. M.; Vinitsky, A.
Journal of Biomolecular Screening (2002), 7 (6), 526-530CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)
FKBP12 is best known as the target of the widely used immunosuppressive drug FK506 but may also play a role in neuronal survival. Nonimmunosuppressive ligands of FKBP12 have been shown to have neuroprotective and neuroregenerative activity both in vitro and in vivo, stimulating interest in the development of high-throughput screens to rapidly identify novel ligands. FKBP12 was expressed as a His6-fusion in bacteria and purified by metal ion affinity and gel filtration chromatog. A high-throughput fluorescence polarization assay was developed to identify novel ligands of FKBP12. Dissocn. const. values of known FKBP12 ligands measured by the new method agreed closely with Ki values obtained by assaying inhibition of the rotamase activity of the enzyme. The fluorescence polarization assay is rapid, robust, and inexpensive and does not generate radioactive waste. It is very well suited for high-throughput screening efforts.
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157
Ye, X. M.; Konradi, A. W.; Smith, J.; Aubele, D. L.; Garofalo, A. W.; Marugg, J.; Neitzel, M. L.; Semko, C. M.; Sham, H. L.; Sun, M.; Truong, A. P.; Wu, J.; Zhang, H.; Goldbach, E.; Sauer, J.-M.; Brigham, E. F.; Bova, M.; Basi, G. S. Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II). Bioorg. Med. Chem. Lett. 2010, 20, 3502– 3506, DOI: 10.1016/j.bmcl.2010.04.148
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157
Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II)
Ye, Xiaocong M.; Konradi, Andrei W.; Smith, Jenifer; Aubele, Danielle L.; Garofalo, Albert W.; Marugg, Jennifer; Neitzel, Marty L.; Semko, Chris M.; Sham, Hing L.; Sun, Minghua; Truong, Anh P.; Wu, Jing; Zhang, Hongbin; Goldbach, Erich; Sauer, John-Michael; Brigham, Elizabeth F.; Bova, Michael; Basi, Guriqbal S.
Bioorganic & Medicinal Chemistry Letters (2010), 20 (12), 3502-3506CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
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158
Xiamuxi, H.; Wang, Z.; Li, J.; Wang, Y.; Wu, C.; Yang, F.; Jiang, X.; Liu, Y.; Zhao, Q.; Chen, W.; Zhang, J.; Xie, Y.; Hu, T.; Xu, M.; Guo, S.; Akber Aisa, H.; He, Y.; Shen, J. Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multi-receptor atypical antipsychotics. Bioorg. Med. Chem. 2017, 25, 4904– 4916, DOI: 10.1016/j.bmc.2017.07.040
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159
(a) Zanda, M. Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New J. Chem. 2004, 28, 1401– 1411, DOI: 10.1039/b405955g
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159a
Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification
Zanda, Matteo
New Journal of Chemistry (2004), 28 (12), 1401-1411CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
A review. Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in the solid phase, for many different fluoroalkyl peptidomimetics, i.e., bis-trifluoromethyl (Tfm) analogs of Pepstatin A, which are nanomolar and selective inhibitors of the protozoal aspartyl protease Plasmepsin II; Tfm-malic peptidomimetics that are micromolar inhibitors of some matrix metalloproteinases; partially modified retro (PMR) and retro-inverso (PMRI) ψ[CH(CF3)NH] peptides with a strong proclivity to assume turn-like conformations; ψ[CH(CF3)NH] peptide mimics having a great potential as hybrids between natural peptides and hydrolytic transition state analogs; PMR peptides incorporating a trifluoroalanine surrogate. These novel classes of fluorinated peptide mimics are likely to represent just the tip of an iceberg formed by new peptidomimetic structures with unique biomedicinal and pharmaceutical properties.
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(b) Sani, M.; Volonterio, A.; Zanda, M. The trifluoroethylamine function as peptide bond replacement. ChemMedChem 2007, 2, 1693– 1700, DOI: 10.1002/cmdc.200700156
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159b
The trifluoroethylamine function as peptide bond replacement
Sani, Monica; Volonterio, Alessandro; Zanda, Matteo
ChemMedChem (2007), 2 (12), 1693-1700CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Synthesis of peptidomimetics contg. a stereogenic trifluoroethylamine group in place of the peptide bond is discussed. Peptidomimetics contg. the trifluoroethylamine group in place of amide group have been found to be highly potent and metabolically stable inhibitors of cathepsin K.
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(c) Brusoe, A. T.; Hartwig, J. F. Palladium-catalyzed arylation of fluoroalkylamines. J. Am. Chem. Soc. 2015, 137, 8460– 8468, DOI: 10.1021/jacs.5b02512
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159c
Palladium-Catalyzed Arylation of Fluoroalkylamines
Brusoe, Andrew T.; Hartwig, John F.
Journal of the American Chemical Society (2015), 137 (26), 8460-8468CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
We report the synthesis of fluorinated anilines by palladium-catalyzed coupling of fluoroalkylamines with aryl bromides and aryl chlorides. The products of these reactions are valuable because anilines typically require the presence of an electron-withdrawing substituent on nitrogen to suppress aerobic or metabolic oxidn., and the fluoroalkyl groups have steric properties and polarity distinct from those of more common electron-withdrawing amide and sulfonamide units. The fluoroalkylaniline products are unstable under typical conditions for C-N coupling reactions (heat and strong base). However, the reactions conducted with the weaker base KOPh, which has rarely been used in cross-coupling to form C-N bonds, occurred in high yields in the presence of a catalyst derived from com. available AdBippyPhos and [Pd(allyl)Cl]2. Under these conditions, the reactions occur with low catalyst loadings (<0.50 mol % for most substrates) and tolerate the presence of various functional groups that react with the strong bases that are typically used in Pd-catalyzed C-N cross-coupling reactions of aryl halides. The resting state of the catalyst is the phenoxide complex, [BippyPhosPd(Ar)OPh]; due to the electron-withdrawing property of the fluoroalkyl substituent, the turnover-limiting step of the reaction is reductive elimination to form the C-N bond.
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160
(a) Volonterio, A.; Bellosta, S.; Bravin, F.; Bellucci, M. C.; Bruche, L.; Colombo, G.; Malpezzi, L.; Mazzini, S.; Meille, S. V.; Meli, M.; Ramirez de Arellano, C.; Zanda, M. Synthesis, structure and conformation of partially-modified retro- and retro-inverso Ψ[NHCH(CF₃)]Gly peptides. Chem. - Eur. J. 2003, 9, 4510– 4522, DOI: 10.1002/chem.200304881
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160a
Synthesis, structure and conformation of partially-modified retro- and retro-inverso ψ[NHCH(CF3)]Gly peptides
Volonterio, Alessandro; Bellosta, Stefano; Bravin, Fabio; Bellucci, Maria Cristina; Bruche, Luca; Colombo, Giorgio; Malpezzi, Luciana; Mazzini, Stefania; Meille, Stefano V.; Meli, Massimiliano; Ramirez de Arellano, Carmen; Zanda, Matteo
Chemistry - A European Journal (2003), 9 (18), 4510-4522CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Partially modified retro- (PMR) and retro-inverso (PMRI) ψ[NHCH(CF3)]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure α-amino esters and peptides with enantiomerically and geometrically pure N-(4,4,4-trifluorocrotonoyl)oxazolidin-2-ones. The factors underlying the obsd. moderate to good diastereocontrol have been investigated. The conformations of model PMR-ψ[NHCH(CF3)]Gly tripeptides have been studied in soln. by 1H NMR spectroscopy supported by MD calcns., as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: (1) severe torsional restrictions about sp3 bonds in the [CO-CH2-CH(CF3)-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF3 group and the R side chain and (2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl3 soln. and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramol. hydrogen bonding. The relative configuration of the -C*H(CF3)NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochem. X-ray diffraction and ab initio computational studies showed that the [-CH(CF3)NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analog, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF3)-NH-CH backbone angle close to 120°, C-CF3 bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O-)NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron d. on the CF3 group, tetrahedral backbone carbon).
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(b) Molteni, M.; Pesenti, C.; Sani, M.; Volonterio, A.; Zanda, M. Fluorinated peptidomimetics: synthesis, conformational and biological features. J. Fluorine Chem. 2004, 125, 1735– 1743, DOI: 10.1016/j.jfluchem.2004.09.014
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160b
Fluorinated peptidomimetics: synthesis, conformational and biological features
Molteni, Marco; Pesenti, Cristina; Sani, Monica; Volonterio, Alessandro; Zanda, Matteo
Journal of Fluorine Chemistry (2004), 125 (11), 1735-1743CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Our interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in solid phase, for many different fluoroalkyl peptidomimetics, some of which are overviewed in this paper: (a) ψ[CH(CF3)NH]-peptide mimics holding a great potential as hybrids between natural peptides and hydrolytic transition state analogs, (b) trifluoromethyl (Tfm) malic peptidomimetics as micromolar inhibitors of some matrix metalloproteinases, and (c) bis-Tfm analogs of pepstatin A, that are nanomolar and selective inhibitors of the protozoal aspartyl protease plasmepsin II.
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(c) Molteni, M.; Bellucci, M. C.; Bigotti, S.; Mazzini, S.; Volonterio, A.; Zanda, M. Ψ[CH(CF₃)NH]Gly-peptides: synthesis and conformation analysis. Org. Biomol. Chem. 2009, 7, 2286– 2296, DOI: 10.1039/b901718f
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160c
Ψ[CH(CF3)NH]Gly-peptides: synthesis and conformation analysis
Molteni, Marco; Bellucci, Maria Cristina; Bigotti, Serena; Mazzini, Stefania; Volonterio, Alessandro; Zanda, Matteo
Organic & Biomolecular Chemistry (2009), 7 (11), 2286-2296CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
Ψ[CH(CF3)NH]Gly peptides, a conceptually new class of peptidomimetics having a stereogenic trifluoroethylamine group as a natural peptide-bond surrogate, have been synthesized by aza-Michael stereoselective addn. of α-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. Long range nuclear Overhauser effects, detected via ROESY expts., provided evidence that model Ψ[CH(CF3)NH]Gly-tetrapeptides incorporating a trifluoroethylamine mimic of the dipeptide loop Pro-Gly can be represented by an ensemble of unfolded and folded conformations. The latter are driven by the formation of a hydrogen bond between a carbonyl group and the aminic proton of the trifluoroethylamine unit. MD calcns. indicate a population of conformers which adopt folded β turn structures for all the L-peptides; on the other hand, a D-stereochem. at the Pro residue induces a natural folding towards a β hairpin conformation driven by the formation of a second hydrogen bond, regardless of the stereochem. of the stereogenic peptide bond surrogate.
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161
(a) Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J.-P.; Leger, S.; Li, C. S.; Massé, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005, 15, 4741– 4744, DOI: 10.1016/j.bmcl.2005.07.071
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161a
Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K
Black, W. Cameron; Bayly, Christopher I.; Davis, Dana E.; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Leger, Serge; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Palmer, James T.; Percival, M. David; Robichaud, Joel; Tsou, Nancy; Zamboni, Robert
Bioorganic & Medicinal Chemistry Letters (2005), 15 (21), 4741-4744CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The nonbasic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compds. are 10- to 20-fold more potent than the corresponding amide derivs. Compd. (I) is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.
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(b) Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.-P.; Gauthier, J. Y.; Kimmel, D. B.; Léger, S.; Massé, F.; McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Thérien, M.; Truong, V.-L.; Wesolowski, G.; Zamboni, R.; Black, W. C. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 2006, 16, 1985– 1989, DOI: 10.1016/j.bmcl.2005.12.071
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161b
Identification of a potent and selective non-basic cathepsin K inhibitor
Li, Chun Sing; Deschenes, Denis; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Gauthier, Jacques Yves; Kimmel, Donald. B.; Leger, Serge; Masse, Frederic; McGrath, Mary E.; McKay, Daniel J.; Percival, M. David; Riendeau, Denis; Rodan, Sevgi B.; Therien, Michel; Truong, Vouy-Linh; Wesolowski, Gregg; Zamboni, Robert; Black, W. Cameron
Bioorganic & Medicinal Chemistry Letters (2006), 16 (7), 1985-1989CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of L-873724 (I) as a potent and selective non-basic cathepsin K inhibitor. This compd. showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The vols. of distribution close to unity were consistent with this compd. not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.
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(c) Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L.T.; Falgueyret, J.-P.; Kimmel, D. B.; Lamontagne, S.; Leger, S.; LeRiche, T.; Li, C. S.; Massé, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.; Truong, V.-L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18, 923– 928, DOI: 10.1016/j.bmcl.2007.12.047
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161c
The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
Gauthier, Jacques Yves; Chauret, Nathalie; Cromlish, Wanda; Desmarais, Sylvie; Duong, Le T.; Falgueyret, Jean-Pierre; Kimmel, Donald B.; Lamontagne, Sonia; Leger, Serge; LeRiche, Tammy; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Nicoll-Griffith, Deborah A.; Oballa, Renata M.; Palmer, James T.; Percival, M. David; Riendeau, Denis; Robichaud, Joel; Rodan, Gideon A.; Rodan, Sevgi B.; Seto, Carmai; Therien, Michel; Truong, Vouy-Linh; Venuti, Michael C.; Wesolowski, Gregg; Young, Robert N.; Zamboni, Robert; Black, W. Cameron
Bioorganic & Medicinal Chemistry Letters (2008), 18 (3), 923-928CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclin. species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
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(d) Mullard, A. Merck & Co. drops osteoporosis drug odanacatib. Nat. Rev. Drug Discovery 2016, 15, 669, DOI: 10.1038/nrd.2016.207
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161d
Merck & Co. drops osteoporosis drug odanacatib
Mullard, Asher
Nature Reviews Drug Discovery (2016), 15 (10), 669CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
A discussion of the osteoporosis drug odanacatib.
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162
Isabel, E.; Mellon, C.; Boyd, M. J.; Chauret, N.; Deschênes, D.; Desmarais, S.; Falgueyret, J. P.; Gauthier, J. Y.; Khougaz, K.; Lau, C. K.; Léger, S.; Levorse, D. A.; Li, C. S.; Massé, F.; Percival, M. D.; Roy, B.; Scheigetz, J.; Thérien, M.; Truong, V. L.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. Difluoroethylamines as an amide isostere in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2011, 21, 920– 923, DOI: 10.1016/j.bmcl.2010.12.070
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Butler, C. R.; Ogilvie, K.; Martinez-Alsina, L.; Barreiro, G.; Beck, E. M.; Nolan, C. E.; Atchison, K.; Benvenuti, E.; Buzon, L.; Doran, S.; Gonzales, C.; Helal, C. J.; Hou, X.; Hsu, M.-H.; Johnson, E. F.; Lapham, K.; Lanyon, L.; Parris, K.; O’Neill, B. T.; Riddell, D.; Robshaw, A.; Vajdos, F.; Brodney, M. A. Aminomethyl-derived beta secretase (BACE-1) inhibitors: engaging Gly230 without an anilide functionality. J. Med. Chem. 2017, 60, 386– 402, DOI: 10.1021/acs.jmedchem.6b01451
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164
(a) Chen, G.; Ren, H.; Turpoff, A.; Arefolov, A.; Wilde, R.; Takasugi, J.; Khan, A.; Almstead, N.; Gu, Z.; Komatsu, T.; Freund, C.; Breslin, J.; Colacino, J.; Hedrick, J.; Weetall, M.; Karp, G. M. Discovery of N-(4′-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication. Bioorg. Med. Chem. Lett. 2013, 23, 3942– 3946, DOI: 10.1016/j.bmcl.2013.04.050
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(b) Zhang, X.; Zhang, N.; Chen, G.; Turpoff, A.; Ren, H.; Takasugi, J.; Morrill, C.; Zhu, J.; Li, C.; Lennox, W.; Paget, S.; Liu, Y.; Almstead, N.; Njoroge, F. G.; Gu, Z.; Komatsu, T.; Clausen, V.; Espiritu, C.; Graci, J.; Colacino, J.; Lahser, F.; Risher, N.; Weetall, M.; Nomeir, A.; Karp, G. M. Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B. Bioorg. Med. Chem. Lett. 2013, 23, 3947– 3953, DOI: 10.1016/j.bmcl.2013.04.049
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Discovery of novel HCV inhibitors: Synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B
Zhang, Xiaoyan; Zhang, Nanjing; Chen, Guangming; Turpoff, Anthony; Ren, Hongyu; Takasugi, James; Morrill, Christie; Zhu, Jin; Li, Chunshi; Lennox, William; Paget, Steven; Liu, Yalei; Almstead, Neil; George Njoroge, F.; Gu, Zhengxian; Komatsu, Takashi; Clausen, Valerie; Espiritu, Christine; Graci, Jason; Colacino, Joseph; Lahser, Fred; Risher, Nicole; Weetall, Marla; Nomeir, Amin; Karp, Gary M.
Bioorganic & Medicinal Chemistry Letters (2013), 23 (13), 3947-3953CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides I [R1 = CHF2O, c-Pr; R2 = i-Pr, H, CH(CH2F)2, etc.] was prepd. and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compds. with low nanomolar potency against the HCV genotype 1b replicon. Among these, compd. I [R1 = CHF2O; R2 = CH(CH2F)2] was identified as a potent HCV replicon inhibitor (EC50 = 4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compd. I [R1 = CHF2O; R2 = CH(CH2F)2] had a good pharmacokinetic profile in rats with an IV half-life of 6 h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compds. These compds. hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.
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(c) Zhang, N.; Zhang, X.; Zhu, J.; Turpoff, A.; Chen, G.; Morrill, C.; Huang, S.; Lennox, W.; Kakarla, R.; Liu, R.; Li, C.; Ren, H.; Almstead, N.; Venkatraman, S.; Njoroge, F. G.; Gu, Z.; Clausen, V.; Graci, J.; Jung, S. P.; Zheng, Y.; Colacino, J. M.; Lahser, F.; Sheedy, J.; Mollin, A.; Weetall, M.; Nomeir, A.; Karp, G.M. Structure–activity relationship (SAR) optimization of 6-(indol-2-yl)pyridine-3-sulfonamides: identification of potent, selective, and orally bioavailable small molecules targeting hepatitis C (HCV) NS4B. J. Med. Chem. 2014, 57, 2121– 2135, DOI: 10.1021/jm401621g
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Fernandez, M. C.; Gonzalez-Garcia, M. R.; Liu, B.; Pfeifer, L. A. Phenyl Methanesulfonamide Derivatives Useful as MGAT-2 Inhibitors. World Patent Application WO-2013/112323 A1, Aug. 1, 2013.
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Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Hiner, R. N.; Dorsey, G. F.; Noe, R. A.; Unwalla, R. J.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; van Arnold, J.; Bickett, D. M.; Moss, M. L.; Tian, G.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Croom, D. K. Structure-activity relationships for inhibition of type 1 and 2 human 5α-reductase and human adrenal 3β-hydroxy-Δ⁵-steroid dehydrogenase/3-keto-Δ⁵-steroid isomerase by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent. J. Med. Chem. 1995, 38, 2621– 2627, DOI: 10.1021/jm00014a015
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(a) di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A. Novel aromatase and 5α-reductase inhibitors. J. Steroid Biochem. Mol. Biol. 1994, 49, 289– 294, DOI: 10.1016/0960-0760(94)90270-4
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Novel aromatase and 5α-reductase inhibitors
Di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A.
Journal of Steroid Biochemistry and Molecular Biology (1994), 49 (4-6), 289-94CODEN: JSBBEZ; ISSN:0960-0760.
Inhibitors of aromatase and 5α-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, resp. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compd. was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compd. was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17β-amidic side chains, three compds., namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5α-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, resp. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compds. were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, resp.
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(b) Giudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Ihelè, C.; Nesi, M.; Panzeri, A.; di Salle, E. FCE 28260, a new 5α-reductase inhibitor: in vitro and in vivo effects. J. Steroid Biochem. Mol. Biol. 1996, 58, 299– 305, DOI: 10.1016/0960-0760(96)00040-4
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167b
FCE 28260, a new 5α-reductase inhibitor: in vitro and in vivo effects
Giudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Iehle, C.; Nesi, M.; Panzeri, A.; di Salle, E.
Journal of Steroid Biochemistry and Molecular Biology (1996), 58 (3), 299-305CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier)
FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compd. causes inhibition of rat and human prostatic enzymes, with IC50 values of 15 an d16 nM, resp., compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5αR type 2 and 1 isoenzymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isoenzymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult rats, FCE 28260 reduced prostatic DHT concns. 6 h after oral dosing with a potency similar to that of finasteride (65% redn. at 1 mg/kg) but was found to be markedly more potent than the ref. compd. at 24 h (74% redn. in prostate DHT at 10 mg/kg, compared to 26% redn. induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.
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(c) di Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Délos, S.; Martin, P. M. PNU 157706, a novel dual type I and II 5α-reductase inhibitor. J. Steroid Biochem. Mol. Biol. 1998, 64, 179– 186, DOI: 10.1016/S0960-0760(97)00158-1
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167c
PNU 157706, a novel dual type I and II 5α-reductase inhibitor
Di Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Delos, S.; Martin, P. M.
Journal of Steroid Biochemistry and Molecular Biology (1998), 64 (3-4), 179-186CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Science Ltd.)
PNU 157706 is a novel dual inhibitor of 5α-reductase (5α-R), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). Tested on a crude prepn. of human or rat prostatic 5α-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, resp., compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5α-R type I and II isoenzymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), particularly on the type I isoenzyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting redn. of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, resp.). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate wt. in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate wt., the ED50 values being 0.12 and 1.9 mg/kg/day, resp. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5α-R with a very marked antiprostatic effect in the rat.
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(d) Basileo, G.; Breda, M.; James, C. A. Determination of PNU-157706, a new dual inhibitor of 5α-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detection. J. Chromatogr., Biomed. Appl. 1998, 719, 191– 197, DOI: 10.1016/S0378-4347(98)00412-5
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167d
Determination of PNU 157706, a new dual inhibitor of 5α-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detection
Basileo, G.; Breda, M.; James, C. A.
Journal of Chromatography B: Biomedical Sciences and Applications (1998), 719 (1 + 2), 191-197CODEN: JCBBEP; ISSN:0378-4347. (Elsevier Science B.V.)
A HPLC procedure was developed and validated for detg. nanogram per mL concns. of the dual 5a-reductase inhibitor PNU 157706 in rat plasma. The compd. was extd. from plasma with di-Et ether followed by purifn. on a CN cartridge. The chromatog. sepn. was performed on a C18 column with water-acetonitrile-methanol mixt. as eluent. UV detection at 210 nm was used for the quantification of the compd. over the concn. range 5-500 ng/mL plasma. The method has a lower limit of quantification of 5 ng/mL and good precision and accuracy. This method performed well during anal. of several toxicokinetic and pharmacokinetic studies in the rat.
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168
(a) Drury, J. E.; Di Costanzo, L.; Penning, T. M.; Christianson, D. W. Inhibition of human steroid 5α-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex. J. Biol. Chem. 2009, 284, 19786– 19790, DOI: 10.1074/jbc.C109.016931
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(b) Karnsomwan, W.; Rungrotmongkol, T.; De-Eknamkul, W.; Chamni, S. chamni, S. In silico prediction of human steroid 5α-reductase type II. Med. Chem. Res. 2016, 25, 1049– 1056, DOI: 10.1007/s00044-016-1541-y
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168b
In silico structural prediction of human steroid 5α-reductase type II
Karnsomwan, Wiranpat; Rungrotmongkol, Thanyada; De-Eknamkul, Wanchai; Chamni, Supakarn
Medicinal Chemistry Research (2016), 25 (6), 1049-1056CODEN: MCREEB; ISSN:1054-2523. (Springer)
Steroid 5α-reductase type II is a membrane-assocd. enzyme in an oxidoreductase family. This enzyme, which is found in male sexual organs, plays the important biol. actions toward steroid metab. Overexpression of 5α-reductase type II has affected the balance between testosterone and dihydrotestosterone, which implicates the androgenic disorders, including prostate cancer, hirsutism, and androgenic alopecia. Lack of single-crystal X-ray structures of 5α-reductase has hindered mechanistic understanding and delayed the discovery and development of an effective inhibitor. Herein, we illustrated a comparative structure of 5α-reductase type II that derived from the homol. modeling, employing a membrane-bound protein, isoprenylcysteine carboxyl methyltransferase as a homologous template. A catalytic pocket and the transmembrane site were identified. The resulting in silico structure was validated via Ramachandran plot and confirmed by docking studies of 30 known 5α-reductase type I and type II inhibitors, including finasteride and dutasteride. The comparative docking study of the derived in silico 5α-reductase type II and 5β-reductase, a reported surrogate enzyme, was conducted. Our homol. model approx. fitted to the membrane-assocd. character and showed the reasonable docking results, which depicted the well-defined comparative three-dimensional structure applicable for steroid reductase drug design.
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169
(a) Howbert, J. J.; Grossman, C. S.; Crowell, T. A.; Rieder, B. J.; Harper, R. W.; Kramer, K. E.; Tao, E. V.; Aikins, J.; Poore, G. A. Novel agents effective against solid tumors: the diarylsulfonylureas. Synthesis, activities, and analysis of quantitative structure-activity relationships. J. Med. Chem. 1990, 33, 2393– 2407, DOI: 10.1021/jm00171a013
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(b) Mohamadi, F.; Spees, M. M.; Grindey, G. B. Sulfonylureas: a new class of cancer chemotherapeutic agents. J. Med. Chem. 1992, 35, 3012– 3016, DOI: 10.1021/jm00094a013
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170
(a) Houghton, P. J.; Houghton, J. A. Antitumor diarylsulfonylureas: novel agents with unfulfilled promise. Invest. New Drugs 1996, 14, 271– 280, DOI: 10.1007/BF00194530
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(b) Owa, T.; Nagasu, T. Novel sulphonamide derivatives for the treatment of cancer. Expert Opin. Ther. Pat. 2000, 10, 1725– 1740, DOI: 10.1517/13543776.10.11.1725
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Novel sulphonamide derivatives for the treatment of cancer
Owa, Takashi; Nagasu, Takeshi
Expert Opinion on Therapeutic Patents (2000), 10 (11), 1725-1740CODEN: EOTPEG; ISSN:1354-3776. (Ashley Publications Ltd.)
A review with 265 refs. is given. The sulfonamides constitute an important class of therapeutic agents in current medicinal science. After the discovery by Gerhard Domagk, of sulphamidochrysoidine (prontosil) as the first antibiotic sulfa-drug an active metabolite of the drug, sulphanilamide, was further derivatized in order to find compds. exhibiting superior antibacterial activity or different pharmacol. effects. Diversification of the sulphanilamide structure led to the serial development of improved antibiotics, insulin-releasing hypoglycemic drugs, carbonic anhydrase- (CA) inhibitory diuretics, anti-hypertensive drugs etc. It is of particular interest that various structurally novel sulfonamide derivs. have recently been reported to show substantial anti-tumor activity in vitro and/or in vivo. Although they have a common chem. motif of an arom./heterocyclic sulfonamide, there are a variety of mechanisms for their anti-tumor action, such as disruption of microtubule assembly, cell cycle arrest in the G1 phase, functional suppression of the transcriptional activator NF-Y, angiogenesis inhibition and carbonic anhydrase inhibition. Furthermore, some of these compds. selected via elaborate preclin. screenings are currently being evaluated in clin. trials. This review summarizes recent patents and related papers which have disclosed novel classes of sulfonamide derivs. for the treatment of cancer.
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(c) Pasello, G.; Urso, L.; Conte, P.; Favaretto, A. Effects of sulfonylureas on tumor growth: a review of the literature. Oncologist 2013, 18, 1118– 1125, DOI: 10.1634/theoncologist.2013-0177
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171
Forouzesh, B.; Takimoto, C. H.; Goetz, A.; Diab, S.; Hammond, L. A.; Smetzer, L.; Schwartz, G.; Gazak, R.; Callaghan, J. T.; Von Hoff, D. D.; Rowinsky, E. K. A Phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies. Clin. Cancer Res. 2003, 9, 5540– 5549
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171
A Phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies
Forouzesh, Bahram; Takimoto, Chris H.; Goetz, Andrew; Diab, Sami; Hammond, Lisa A.; Smetzer, Leslie; Schwartz, Garry; Gazak, Robert; Callaghan, John T.; Von Hoff, Daniel D.; Rowinsky, Eric K.
Clinical Cancer Research (2003), 9 (15), 5540-5549CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
This study was conducted to assess the feasibility of administering the oral diarylsulfonylurea (DSU) ILX-295501 on a weekly for 3 wk every 4-wk schedule. The study also sought to det. the max. tolerated dose (MTD) of ILX-295501 on this schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. The initial starting dose of ILX-295501 was 100 mg/m2, which was equiv. to one-sixth of the highest dose that did not induce irreversible toxicity in dogs, and, using a modified Fibonnaci search scheme to guide dose level selection, the following dose levels were evaluated: 100, 200, 400, 600, 900, 1350, and 1800 mg/m2. Because severe toxicities were being reported in other trials at doses that encompassed this range and a cumulative toxicity profile was emerging, the study was suspended and then reinitiated to further reevaluate the lower dosing range. In the second part of the study, the following dose levels were selected a priori for evaluation: 400, 800, 1000, 1250, and 1500 mg/m2; and a modified continual reassessment model was used for dose assignment to det. the MTD, which was defined a priori as the highest dose in which the incidence of dose-limiting toxicity in the first course did not exceed 20%. Forty-nine patients were treated with 142 courses of ILX-295501 at doses ranging from 100 to 1800 mg/m2. The incidences of dose-limiting toxicity, principally neutropenia and thrombocytopenia, were unacceptably high at ILX-295501 doses exceeding 1000 mg/m2, which was detd. to be the MTD for both minimally pretreated and heavily pretreated (HP) patients. In contrast to the first generation of DSUs, particularly sulofenur, clin. relevant levels of oxidized Hb (metHb) and secondary hemolytic anemia, were not noted. One HP patient with non-small cell lung carcinoma experienced a partial response. Pharmacokinetic studies revealed that ILX-295501 was absorbed slowly, with peak plasma concns. (Cmax) achieving 6.02 h, on av., after oral administration. The pharmacokinetic behavior of ILX-295501 was characterized by dose proportionality, a relatively small apparent vol. of distribution at steady state (Vss/F), averaging 8.02 ± 14.08 L, and low apparent total body clearance (CLt/F) rate (mean, 0.036 ± 0.116 L/h). The initial drug distribution phase was rapid [harmonic mean half-life (t1/2α), 2.1±7.0 min], whereas the terminal elimination phase was slow (harmonic mean t1/2β, 150.6 ± 80.2 h). The recommended dose for Phase II studies of the oral DSU ILX-295501 administered weekly for 3 wk every 4 wk is 1000 mg/m2/day for both minimally pretreated and HP patients. The characteristics of the myelosuppressive effects of ILX-295501, the paucity of severe nonhematol. toxicities, and preliminary antitumor activity warrant disease-directed evaluations of ILX-295501.
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172
(a) Toth, J. E.; Grindey, G. B.; Ehlhardt, W. J.; Ray, J. E.; Boder, G. B.; Bewley, J. R.; Klingerman, K. K.; Gates, S. B.; Rinzel, S. M.; Schultz, R. M.; Weir, L. C.; Worzalla, J. F. Sulfonimidamide analogs of oncolytic sulfonylureas. J. Med. Chem. 1997, 40, 1018– 1025, DOI: 10.1021/jm960673l
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172a
Sulfonimidamide Analogs of Oncolytic Sulfonylureas
Toth, John E.; Grindey, Gerald B.; Ehlhardt, William J.; Ray, James E.; Boder, George B.; Bewley, Jesse R.; Klingerman, Kim K.; Gates, Susan B.; Rinzel, Sharon M.; Schultz, Richard M.; Weir, Leonard C.; Worzalla, John F.
Journal of Medicinal Chemistry (1997), 40 (6), 1018-1025CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A series of sulfonimidamide analogs of the oncolytic diarylsulfonylureas was synthesized and evaluated for in vitro cytotoxicity against CEM cells, in vivo antitumor activity against subaxillary implanted 6C3HED lymphosarcoma, and metabolic breakdown to the o-sulfate of p-chloroaniline. The sepd. enantiomers of 1 sulfonimidamide analog displayed very different activities in the in vivo screening model. In general, several analogs demonstrated excellent growth inhibitory activity in the 6C3HED model when dosed orally or i.p. A correlative structure-activity relationship to the oncolytic sulfonylureas was not apparent.
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(b) Chern, J. W.; Leu, Y. L.; Wang, S. S.; Jou, R.; Lee, C. F.; Tsou, P. C.; Hsu, S. C.; Liaw, Y. C.; Lin, H. M. Synthesis and cytotoxic evaluation of substituted sulfonyl-N-hydroxyguanidine derivatives as potential antitumor agents. J. Med. Chem. 1997, 40, 2276– 2286, DOI: 10.1021/jm9607818
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173
(a) Luzina, E. L.; Popov, A. V. Synthesis and anticancer activity of N-bis(trifluoromethyl)alkyl-N′-thiazolyl and N-bis(trifluoromethyl)alkyl-N′-benzothiazolyl ureas. Eur. J. Med. Chem. 2009, 44, 4944– 4953, DOI: 10.1016/j.ejmech.2009.08.007
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Métayer, B.; Compain, G.; Jouvin, K.; Martin-Mingot, A.; Bachmann, C.; Marrot, J.; Evano, G.; Thibaudeau, S. Chemo- and stereo-selective synthesis of fluorinated enamides from ynamides in HF/pyridine: second-generation approach to potent ureas bioisosteres. J. Org. Chem. 2015, 80, 3397– 3410, DOI: 10.1021/jo502699y
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175
(a) Mewshaw, R. E.; Marquis, K. L.; Shi, X.; McGaughey, G.; Stack, G.; Webb, M. B.; Abou-Gharbia, M.; Wasik, T.; Scerni, R.; Spangler, T.; Brennan, J. A.; Mazandarani, H.; Coupet, J.; Andree, T. H. New generation dopaminergic agents 4. Exploiting the 2-methyl chroman scaffold. Synthesis and evaluation of two novel series of 2-(aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano [2,3-e]indole and indol-8-one derivatives. Tetrahedron 1998, 54, 7081– 7108, DOI: 10.1016/S0040-4020(98)00349-4
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(b) Mewshaw, R. E.; Verwijs, A.; Shi, X.; McGaughey, G. B.; Nelson, j. A.; Mazandarani, H.; Brennan, J. A.; Marquis, K. L.; Coupet, J.; Andree, T. H. New generation dopaminergic agents. 5. Heterocyclic bioisosteres that exploit the 3-OH-N1-phenylpiperazine dopaminergic template. Bioorg. Med. Chem. Lett. 1998, 8, 2675– 2680, DOI: 10.1016/S0960-894X(98)00474-0
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New generation dopaminergic agents. 5. heterocyclic bioisosteres that exploit the 3-OH-N'-phenylpiperazine dopaminergic template
Mewshaw, Richard E.; Verwijs, Antoine; Shi, Xiaojie; Mcgaughey, Georgia B.; Nelson, James A.; Mazandarani, Hossein; Brennan, Julie A.; Marquis, Karen L.; Coupet, Joseph; Andree, Terrance H.
Bioorganic & Medicinal Chemistry Letters (1998), 8 (19), 2675-2680CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
The synthesis of several bioisosteric analogs based on the 3-OH-N'-phenylpiperazine dopamine D2 agonist template is described. The indolone (I) and 2-CF3-benzimidazole (II) were obsd. to have excellent affinity for the D2 receptor. Several D4 selective compds. were also identified. Mol. modeling studies and a putative bioactive conformation are discussed.
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(c) Mewshaw, R. E.; Nelson, J. A.; Shah, U. S.; Shi, X.; Mazandarani, H.; Coupet, J.; Marquis, K.; Brennan, J. A.; Andree, T. H. New generation dopaminergic agents. 7. Heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D₂ template. Bioorg. Med. Chem. Lett. 1999, 9, 2593– 2598, DOI: 10.1016/S0960-894X(99)00434-5
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(d) Mewshaw, R. E.; Zhao, R.; Shi, X.; Marquis, K.; Brennan, J. A.; Mazandarani, H.; Coupet, J.; Andree, T. H. New generation dopaminergic agents. Part 8: heterocyclic bioisosteres that exploit the 7-OH-2-(aminomethyl)chroman D₂ template. Bioorg. Med. Chem. Lett. 2002, 12, 271– 274, DOI: 10.1016/S0960-894X(01)00778-8
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176
Banks, J. W.; Batsanov, A. S.; Howard, J. A. K.; O’Hagan, D.; Rzepa, H. S.; Martin-Santamaria, S. The preferred conformation of α-fluoroamides. J. Chem. Soc., Perkin Trans. 2 1999, 2409– 2411, DOI: 10.1039/a907452j
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The preferred conformation of α-fluoroamides
Banks, John W.; Batsanov, Andrei S.; Howard, Judith A. K.; O'Hagan, David; Rzepa, Henry S.; Martin-Santamaria, Sonsoles
Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1999), (11), 2409-2411CODEN: JCPKBH; ISSN:0300-9580. (Royal Society of Chemistry)
X-Ray structures of two α-fluoroamide derivs. show the O:C-C-F moiety tending towards a trans planar conformation, for which ab initio calcns. suggest a deep (up to 8 kcal mol-1) potential min.
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177
Olivato, P. R.; Guerrero, S. A.; Yreijo, M. H.; Rittner, R.; Tormena, C. F. Conformational and electronic interaction studies of 2-fluoro-substituted N,N-dimethylamides. J. Mol. Struct. 2002, 607, 87– 99, DOI: 10.1016/S0022-2860(01)00761-X
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Briggs, C. R. S.; O’Hagan, D.; Howard, J. A. K.; Yufit, D. S. The C-F bond as a tool in the conformational control of amides. J. Fluorine Chem. 2003, 119, 9– 13, DOI: 10.1016/S0022-1139(02)00243-9
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The C-F bond as a tool in the conformational control of amides
Briggs, Caroline R. S.; O'Hagan, David; Howard, Judith A. K.; Yufit, Dmitrii S.
Journal of Fluorine Chemistry (2003), 119 (1), 9-13CODEN: JFLCAR; ISSN:0022-1139. (Elsevier Science B.V.)
The conformation of 2-fluoro-N-(2-fluoroethyl)-propionamide 4 in the solid state indicates the influence of both a β-F-amide gauche effect and an α-fluoroamide effect. The structure reveals the influence of two recently obsd. stereoelectronic effects assoc. with the C-F bond, which resulted in the successful prediction of the solid state conformation of amide 4. A gauche relation (-69.9°) was obsd. for atoms N(1)-C(4)-C(5)-F and a syn planar (2.0°) relation was obsd. for N(1)-C(3)-C(2)-F. The paper demonstrates the predictive power of using the C-F bond as a tool in influencing the conformation of amides and peptides.
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179
Winkler, M.; Moraux, T.; Khairy, H. A.; Scott, R. H.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and vanilloid receptor (TRPV1) activity of the enantiomers of α-fluorinated capsaicin. ChemBioChem 2009, 10, 823– 828, DOI: 10.1002/cbic.200800709
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180
(a) Jones, C. R.; Baruah, P. K.; Thompson, A. L.; Scheiner, S.; Smith, M. D. Can. a C–H···O interaction be a determinant of conformation?. J. Am. Chem. Soc. 2012, 134, 12064– 12071, DOI: 10.1021/ja301318a
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(b) Driver, R. W.; Claridge, T. D. W.; Scheiner, S.; Smith, M. D. Torsional and electronic factors control the C–H···O interaction. Chem. - Eur. J. 2016, 22, 16513– 16521, DOI: 10.1002/chem.201602905
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180b
Torsional and Electronic Factors Control the C-H...O Interaction
Driver, Russell W.; Claridge, Timothy D. W.; Scheiner, Steve; Smith, Martin D.
Chemistry - A European Journal (2016), 22 (46), 16513-16521CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The precise role of nonconventional hydrogen bonds such as the C-H...O interaction in influencing the conformation of small mols. remains unresolved. Here the authors survey β-turn mimetics using x-ray crystallog. and NMR spectroscopy in conjunction with quantum calcn., and conclude that favorable torsional and electronic effects are important for the population of states with conformationally influential C-H...O interactions. Results also highlight the challenge in attempting to deconvolute a myriad of interdependent noncovalent interactions to focus on the contribution of a single one. Within a small mol. that is designed to resemble the complexity of the environment within peptides and proteins, the interplay of different steric burdens, hydrogen-acceptor/-donor properties and rotational profiles illustrate why unambiguous conclusions based solely on NMR chem. shift data are extremely challenging to rationalize.
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(c) Koeller, S.; Thomas, C.; Peruch, F.; Deffieux, A.; Massip, S.; Léger, J.-M.; Desvergne, J.-P.; Milet, A.; Bibal, B. α-Halogenoacetanilides as hydrogen-bonding organocatalysts that activate carbonyl bonds: fluorine versus chlorine and bromine. Chem. - Eur. J. 2014, 20, 2849– 2859, DOI: 10.1002/chem.201303662
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180c
α-Halogenoacetanilides as Hydrogen-Bonding Organocatalysts that Activate Carbonyl Bonds: Fluorine versus Chlorine and Bromine
Koeller, Sylvain; Thomas, Coralie; Peruch, Frederic; Deffieux, Alain; Massip, Stephane; Leger, Jean-Michel; Desvergne, Jean-Pierre; Milet, Anne; Bibal, Brigitte
Chemistry - A European Journal (2014), 20 (10), 2849-2859CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
α-Halogenoacetanilides (X = F, Cl, Br) with substituents on the Ph ring were examd. as H-bonding organocatalysts designed for the double activation of C=O bonds through NH and CH donor groups. Depending on the halide substituents, the double H-bond involved a nonconventional C···H···O interaction with either a H-CXn (n= 1-2, X = Cl, Br) or a H-CAr bond (X = F), as shown in the solid-state crystal structures and by mol. modeling. In addn., the catalytic properties of α-haloacetanilides were evaluated in the ring-opening polymn. of lactide, in the presence of a tertiary amine as cocatalyst. The α-dichloro- and α-dibromoacetanilides contg. electron-deficient arom. groups afforded the most attractive double H-bonding properties towards C=O bonds, with a N-H···O···H···CX2 interaction.
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(d) Jaun, B.; Seebach, D.; Mathad, R. I. Note: Helix or no helix of β-peptides containing β³hAla(αF) residues?. Helv. Chim. Acta 2011, 94, 355– 361, DOI: 10.1002/hlca.201100023
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(e) Chekhlov, A. N.; Aksinenko, A. Yu.; Pushin, A. N.; Sokolov, V. B. An unusually strong intramolecular C-H•••N hydrogen bond in 3-(α-hydroperfluoroisobutyryl)-2-[(α-hydroperfluoroisobutyryl)imino]-1,3-thiazolidine. Russ. Chem. Bull. 1995, 44, 1531– 1532, DOI: 10.1007/BF00714447
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(f) Chekhlov, A. N. Crystal and molecular structure of 3-(α-hydroperfluoroisobutyryl)-2-[(α-hydroperfluoroisobutyryl)imino]-1,3-thiazolidine with an unusually short intramolecular C-H•••N hydrogen bond. Kristallografiya 1995, 842– 847
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180f
Crystal and molecular structure of 3-(α-hydroperfluoroisobutyryl)-2-(α-hydroperfluoroisobutyryl)imino-1,3-thiazolidine with an unusually short intramolecular C-H···N hydrogen bond
Chekhlov, A. N.
Kristallografiya (1995), 40 (5), 842-7CODEN: KRISAJ; ISSN:0023-4761. (MAIK Nauka)
The title compd. is monoclinic, space group P21/n, with a 9.203(1), b 10.349(1), c 17.299(2) Å, and β 95.74(1)°; Z = 4, dc = 1.857; R = 0.059 for 2075 reflections. At. coordinates are given. The 5-membered thiazolidine ring has half-chair conformation. This mol. has an unusually short H bond C-H...N with H...N distance 2.00(3) Å. The mol. also has a significantly shortened contact S...O 2.652(2) Å, with nonvalent interaction between S and O atoms. In the crystal structure, the mols. are connected in centrosym. dimer pairs with intermol. H bonds of C-H...O type with H...O distance of 2.38(3) Å.
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(g) Brewitz, L.; Arteaga Arteaga, F.; Yin, L.; Alagiri, K.; Kumagai, N.; Shibasaki, M. Direct catalytic asymmetric Mannich-type reaction of α- and β-fluorinated amides. J. Am. Chem. Soc. 2015, 137, 15929– 15939, DOI: 10.1021/jacs.5b11064
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180g
Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated Amides
Brewitz, Lennart; Arteaga, Fernando Arteaga; Yin, Liang; Alagiri, Kaliyamoorthy; Kumagai, Naoya; Shibasaki, Masakatsu
Journal of the American Chemical Society (2015), 137 (50), 15929-15939CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amts. of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivs. for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-contg. small mols., α- and β-fluorinated carbonyl compds. have been neglected in direct enolization chem. because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Bronsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chem.
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(h) Brewitz, L.; Noda, H.; Kumagai, N.; Shibasaki, M. Structural and computational investigation of intramolecular N•••H interactions in α- and β-fluorinated 7-azaindoline amides. Eur. J. Org. Chem. 2017, DOI: 10.1002/ejoc.201701083
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181
Jones, C. R.; Dan Pantos, G. D.; Morrison, A. J.; Smith, M. D. Plagiarizing proteins: enhancing efficiency in asymmetric hydrogen-bonding catalysis through positive cooperativity. Angew. Chem., Int. Ed. 2009, 48, 7391– 7394, DOI: 10.1002/anie.200903063
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181
Plagiarizing Proteins: Enhancing Efficiency in Asymmetric Hydrogen-Bonding Catalysis through Positive Cooperativity
Jones, Christopher R.; Dan Pantos, G.; Morrison, Angus J.; Smith, Martin D.
Angewandte Chemie, International Edition (2009), 48 (40), 7391-7394, S7391/1-S7391/127CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A hairpin turn intramol. H-bonded thiourea-urea catalyst was proficient in the highly enantioselective Mukaiyama-Mannich reaction of arom. BOC-aldimines with silyl ketene acetal nucleophile, providing β-aryl β-amino acids in 97 to >99% ee. Deletion of the urea H-bond donor group revealed that the effect of conformational ordering on the asym. induction is significant but relatively small. The intramol. H-bonded catalyst out-competed the urea-deleted catalyst in a competition reaction, suggesting tighter ligand-receptor binding in the transition state and tighter noncovalent interactions in the former case, and also exhibited higher anion-binding ability - consistent with cooperative ligand binding.
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182
Unione, L.; Alcalá, M.; Echeverria, B.; Serna, S.; Ardá, A.; Franconetti, A.; Cañada, F. J.; Diercks, T.; Reichardt, N.; Jiménez-Barbero, J. Fluoroacetamide moieties as NMR spectroscopy probes for the molecular recognition of GlcNAc-containing sugars: modulation of the CH−π stacking interactions by different fluorination patterns. Chem. - Eur. J. 2017, 23, 3957– 3965, DOI: 10.1002/chem.201605573
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182
Fluoroacetamide Moieties as NMR Spectroscopy Probes for the Molecular Recognition of GlcNAc-Containing Sugars: Modulation of the CH-π Stacking Interactions by Different Fluorination Patterns
Unione, Luca; Alcala, Maria; Echeverria, Begona; Serna, Sonia; Arda, Ana; Franconetti, Antonio; Canada, F. Javier; Diercks, Tammo; Reichardt, Niels; Jimenez-Barbero, Jesus
Chemistry - A European Journal (2017), 23 (16), 3957-3965CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
We herein propose the use of fluoroacetamide and difluoroacetamide moieties as sensitive tags for the detection of sugar-protein interactions by simple 1H and/or 19F NMR spectroscopy methods. In this process, we have chosen the binding of N,N'-diacetyl chitobiose, a ubiquitous disaccharide fragment in glycoproteins, by wheat-germ agglutinin (WGA), a model lectin. By using satn.-transfer difference (STD)-NMR spectroscopy, we exptl. demonstrate that, under soln. conditions, the mol. that contained the CHF2CONH- moiety is the stronger arom. binder, followed by the analog with the CH2FCONH- group and the natural mol. (with the CH3CONH- fragment). In contrast, the mol. with the CF3CONH- isoster displayed the weakest intermol. interaction (one order of magnitude weaker). Because sugar-arom. CH-π interactions are at the origin of these observations, these results further contribute to the characterization and exploration of these forces and offer an opportunity to use them to unravel complex recognition processes.
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183
(a) Depreux, P.; Lesieur, D.; Mansour, H. A.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola, B.; Yous, S.; Demarque, A.; Adam, G.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J. Med. Chem. 1994, 37, 3231– 3239, DOI: 10.1021/jm00046a006
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183a
Synthesis and Structure-Activity Relationships of Novel Naphthalenic and Bioisosteric Related Amidic Derivatives as Melatonin Receptor Ligands
Depreux, Patrick; Lesieur, Daniel; Mansour, Hamid Ait; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; et al.
Journal of Medicinal Chemistry (1994), 37 (20), 3231-9CODEN: JMCMAR; ISSN:0022-2623.
A series of N-naphthylethyl amide derivs. were synthesized and evaluated as melatonin receptor ligands. The affinity of each compd. for the melatonin receptor was detd. by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent on the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analog was a poor ligand. N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, a selective ligand of the melatonin receptor and an agonist deriv., has been selected for clin. development.
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(b) Leclerc, V.; Fourmaintraux, E.; Depreux, P.; Lesieur, D.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola-Lemaître, B.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Bioorg. Med. Chem. 1998, 6, 1875– 1887, DOI: 10.1016/S0968-0896(98)00147-3
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183b
Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands
Leclerc, Veronique; Fourmaintraux, Eric; Depreux, Patrick; Lesieur, Daniel; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; Guardiola-Lemaitre, Beatrice; Andrieux, Jean
Bioorganic & Medicinal Chemistry (1998), 6 (10), 1875-1887CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)
A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogs of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n-Pr urea deriv. is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This mol., a Pr deriv., or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclin. development.
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(c) Ettaoussi, M.; Sabaouni, A.; Rami, M.; Boutin, J. A.; Delagrange, P.; Renard, P.; Spedding, M.; Caignard, D.-H.; Berthelot, P.; Yous, S. Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT₁/MT₂) and serotoninergic 5-HT_2C dual ligands (I). Eur. J. Med. Chem. 2012, 49, 310– 323, DOI: 10.1016/j.ejmech.2012.01.027
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(d) Zlotos, D. P.; Riad, N. M.; Osman, M. B.; Dodda, B. R.; Witt-Enderby, P. A. Novel difluoroacetamide analogues of agomelatine and melatonin: probing the melatonin receptors for MT1 selectivity. MedChemComm 2015, 6, 1340– 1344, DOI: 10.1039/C5MD00190K
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184
Qiu, X.-L.; Xu, X.-H.; Qing, F.-L. Recent advances in the synthesis of fluorinated nucleosides. Tetrahedron 2010, 66, 789– 843, DOI: 10.1016/j.tet.2009.11.001
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185
Noble, S.; Goa, K. L. Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs 1997, 54, 447– 472, DOI: 10.2165/00003495-199754030-00009
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185
Gemcitabine. A review of its pharmacology and clinical potential in non-small-cell lung cancer and pancreatic cancer
Noble, Stuart; Goa, Karen L.
Drugs (1997), 54 (3), 447-472CODEN: DRUGAY; ISSN:0012-6667. (Adis)
A review with 119 refs. Gemcitabine is a deoxycytidine analog which was originally investigated for its antiviral effects but has since been developed as an anticancer therapy. Gemcitabine monotherapy produced an objective tumor response in 18-26% of patients with advanced non-small-cell lung cancer (NSCLC) and appears to have efficacy similar to that of cisplatin plus etoposide. Objective response rates ranging 26-54% were recorded when gemcitabine was combined with cisplatin, and 1-yr survival duration after such treatment ranged 35-61%. Improvements in a range of NSCLC disease symptoms and/or in general performance status occurred in many patients who received gemcitabine, with or without cisplatin, in 3 clin. trials. Gemcitabine appears to be cost effective compared with best supportive care for NSCLC. In addn., direct costs assocd. with administration of gemcitabine monotherapy may be lower than those for some other NSCLC chemotherapy options. The combination of gemcitabine plus cisplatin was assocd. with a lower cost-per-tumor response than cisplatin plus etoposide or cisplatin plus vinorelbine, according to a retrospective cost-effectiveness anal. In a single comparative study in patients with advanced pancreatic cancer, gemcitabine was more effective than fluorouracil with respect to survival duration and general clin. status. It also showed modest antitumor and palliative efficacy in patients refractory to fluorouracil. Gemcitabine appears to be well tolerated, although further comparisons with other chemotherapy regimens are required. The data indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide in patients with NSCLC. Data from noncomparative studies suggest that the combination of gemcitabine and cisplatin has an acceptable tolerability profile. In a single trial in patients with pancreatic cancer, fluorouracil was better tolerated than gemcitabine; however, gemcitabine was generally well tolerated overall in this study. Thus, gemcitabine (with or without cisplatin) may prove attractive to patients with advanced NSCLC, given their limited life expectancy and the toxicity assocd. with many other chemotherapy regimens. Gemcitabine is a valuable new chemotherapy option for patients with advanced pancreatic cancer, a disease considered incurable at present. Its apparent survival and palliative benefits over fluorouracil require confirmation, but are encouraging, as the need to improve both the duration and quality of survival in these patients is well recognized.
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186
Hui, C. K.; Lau, G.K. K. Clevudine for the treatment of chronic hepatitis B virus infection. Expert Opin. Invest. Drugs 2005, 14, 1277– 1284, DOI: 10.1517/13543784.14.10.1277
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187
(a) Sofia, M. J.; Bao, S.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.-R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A. M.; Micolochick Steur, H. M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-D-2′deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis c virus. J. Med. Chem. 2010, 53, 7202– 7218, DOI: 10.1021/jm100863x
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(b) Appleby, T. C.; Perry, J. K.; Murakami, E.; Barauskas, O.; Feng, J.; Cho, A.; Fox, D., III; Wetmore, D. R.; McGrath, M. E.; Ray, A. S.; Sofia, M. J.; Swaminathan, S.; Edwards, T. E. Structural basis for RNA replication by the hepatitis C virus polymerase. Science 2015, 347, 771– 775, DOI: 10.1126/science.1259210
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187b
Structural basis for RNA replication by the hepatitis C virus polymerase
Appleby, Todd C.; Perry, Jason K.; Murakami, Eisuke; Barauskas, Ona; Feng, Joy; Cho, Aesop; Fox, David, III; Wetmore, Diana R.; McGrath, Mary E.; Ray, Adrian S.; Sofia, Michael J.; Swaminathan, S.; Edwards, Thomas E.
Science (Washington, DC, United States) (2015), 347 (6223), 771-775CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Nucleotide analog inhibitors have shown clin. success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by detg. crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our anal. revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A β loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clin. active metabolite formed by sofosbuvir, to elucidate key mol. interactions in the active site.
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188
Van Roey, P.; Salerno, J. M.; Chu, C.-K.; Schinazi, R. F. Correlation between preferred sugar ring conformation and activity of nucleoside analogues against human immunodeficiency virus. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 3929– 3933, DOI: 10.1073/pnas.86.11.3929
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189
Gore, K. R.; Harikrishna, S.; Pradeepkumar, P. I. Influence of 2′-fluoro versus 2′-O-methyl substituent on the sugar puckering of 4′-C-aminomethyluridine. J. Org. Chem. 2013, 78, 9956– 9962, DOI: 10.1021/jo4012333
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190
Zeng, D.; Zhang, R.; Nie, Q.; Cao, L.; Shang, L.; Yin, Z. Discovery of 2′-α-C-methyl-2′-β-C-fluorouridine phosphoramidate prodrugs as inhibitors of hepatitis C virus. ACS Med. Chem. Lett. 2016, 7, 1197– 1201, DOI: 10.1021/acsmedchemlett.6b00270
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191
Pallan, P. S.; Prakash, T. P.; de Leon, A. R.; Egli, M. Limits of RNA 2′-OH mimicry by fluorine: crystal structure of bacillus halodurans RNase H bound to a 2′-FRNA:DNA hybrid. Biochemistry 2016, 55, 5321– 5325, DOI: 10.1021/acs.biochem.6b00849
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191
Limits of RNA 2'-OH mimicry by fluorine: Crystal structure of Bacillus halodurans RNase H bound to a 2'-FRNA:DNA hybrid
Pallan, Pradeep S.; Prakash, Thazha P.; de Leon, Arnie R.; Egli, Martin
Biochemistry (2016), 55 (38), 5321-5325CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
RNase H1 cleaves the RNA strand of RNA:DNA hybrids. Replacement of RNA 2'-OH groups by F (FRNA) is commonly used to stabilize aptamers and siRNAs. However, FRNA:DNA hybrids fail to elicit RNase H1 activity. The underlying reasons are unclear, as 2'-OH groups are not directly involved in cleavage. Here, the authors detd. the crystal structure of Bacillus halodurans RNase H1 bound to a FRNA:DNA hybrid. The structure pointed to dynamic (slippage of the FRNA:DNA hybrid relative to the enzyme), geometric (different curvatures of FRNA:DNA and RNA:DNA hybrids), and electronic reasons (Mg2+ absent from the active site of the FRNA:DNA complex) for the loss of RNase H1 activity.
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192
(a) Hinderaker, M. P.; Raines, R. T. An electronic effect on protein structure. Protein Sci. 2003, 12, 1188– 1194, DOI: 10.1110/ps.0241903
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192a
An electronic effect on protein structure
Hinderaker, Matthew P.; Raines, Ronald T.
Protein Science (2003), 12 (6), 1188-1194CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)
The well-known preference of the peptide bond for the trans conformation has been attributed to steric effects. Here, we show that a proline residue with an N-formyl group (Hi-1-C'i-1=Oi-1), in which Hi-1 presents less steric hindrance than does Oi-1, likewise prefers a trans conformation. Thus, the preference of the peptide bond for the trans conformation cannot be explained by steric effects alone. Rather, an n → π* interaction between the oxygen of the peptide bond (Oi-1), and the subsequent carbonyl carbon in the polypeptide chain (C'i) also contributes to this preference. The Oi-1 and C'i distance and Oi-1···C'i=Oi angle are esp. favorable for such an n → π* interaction in a polyproline II helix. We propose that this electronic effect provides substantial stabilization to this and other elements of protein structure.
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(b) Horng, J.-C.; Raines, R. T. Stereoelectronic effects on polyproline conformation. Protein Sci. 2006, 15, 74– 83, DOI: 10.1110/ps.051779806
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192b
Stereoelectronic effects on polyproline conformation
Horng, Jia-Cherng; Raines, Ronald T.
Protein Science (2006), 15 (1), 74-83CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)
The polyproline type II (PPII) helix is a prevalent conformation in both folded and unfolded proteins, and is known to play important roles in a wide variety of biol. processes. Polyproline itself can also form a type I (PPI) helix, which has a disparate conformation. Here, we use derivs. of polyproline, (Pro)10, (Hyp)10, (Flp)10, and (flp)10, where Hyp is (2S,4R)-4-hydroxyproline, Flp is (2S,4R)-4-fluoroproline, and flp is (2S,4S)-4-fluoroproline, to probe for a stereoelectronic effect on the conformation of polyproline. CD spectral analyses show that 4R electron-withdrawing substituents stabilize a PPII helix relative to a PPI helix, even in a solvent that favors the PPI conformation, such as n-propanol. The stereochem. at C4 ordains the relative stability of PPI and PPII helixes, as (flp)10 forms a mixt. of PPI and PPII helixes in water and a PPI helix in n-propanol. The conformational preferences of (Pro)10 are intermediate between those of (Hyp)10/(Flp)10 and (flp)10. Interestingly, PPI helixes of (flp)10 exhibit cold denaturation in n-propanol with a value of Ts near 70°. Together, these data show that stereoelectronic effects can have a substantial impact on polyproline conformation and provide a rational means to stabilize a PPI or PPII helix.
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(c) Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.; Raines, R. T. Conformational stability of collagen relies on a stereoelectronic effect. J. Am. Chem. Soc. 2001, 123, 777– 778, DOI: 10.1021/ja005542v
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192c
Conformational Stability of Collagen Relies on a Stereoelectronic Effect
Bretscher, Lynn E.; Jenkins, Cara L.; Taylor, Kimberly M.; DeRider, Michele L.; Raines, Ronald T.
Journal of the American Chemical Society (2001), 123 (4), 777-778CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Here, we demonstrate for the first time that a stereoelectronic effect is crit. for the conformational stability of a protein.
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193
Bacqué, E. Influence of fluorination at position 16 of antibacterial pristinamycins II. Chimia 2004, 58, 128– 132, DOI: 10.2533/000942904777678109
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194
Erickson, J.; McLoughlin, J. I. Hydrogen bond donor properties of the difluoromethyl group. J. Org. Chem. 1995, 60, 1626– 1631, DOI: 10.1021/jo00111a021
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194
Hydrogen Bond Donor Properties of the Difluoromethyl Group
Erickson, Jon A.; McLoughlin, Jim I.
Journal of Organic Chemistry (1995), 60 (6), 1626-31CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A theor. and exptl. study of the existence and the properties of the difluoromethyl group acting as a hydrogen bond donor has been carried out. An intramol. CF2H...O:C interaction was examd. using semiempirical MO calcns. of both a non-hydrogen-bonded and hydrogen-bonded conformation of a CF2H-substituted pyrazolecarboxamide fungicide. Results revealed a short H...O contact, a significant energy stabilization, and a lowering in the IR spectrum of 22 cm-1. The exptl. IR spectrum of this mol. gave two carbonyl stretching frequencies, one lower by 18 cm-1, very similar to the calcd. no. Low-temp. NMR results are also consistent with a geometry having the possibility of an intramol. CF2H...O:C hydrogen bond. The hydrogen bond in this system may be related to the enhanced biol. activity of the CF2H compd. over its CF3 counterpart. In addn., ab initio MO methods were employed to examine inter- and intramol. hydrogen-bonding models of the difluoromethyl group. The results showed that the CF2H...O:C interaction has a binding energy of ∼1.0 kcal mol-1 and a H...O distance of ∼2.4 Å.
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195
(a) Walter, H.; Tobler, H.; Gribkov, D.; Corsi, D. Sedaxane, isopyrazam and solatenol: novel broad-spectrum fungicides inhibiting succinate dehydrogenase (SDH) - synthesis challenges and biological aspects. Chimia 2015, 69, 425– 434, DOI: 10.2533/chimia.2015.425
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(b) Jeschke, P. Progress of modern agricultural chemistry and future prospects. Pest Manage. Sci. 2016, 72, 433– 455, DOI: 10.1002/ps.4190
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195b
Progress of modern agricultural chemistry and future prospects
Jeschke, Peter
Pest Management Science (2016), 72 (3), 433-455CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)
Agriculture is facing an enormous challenge: it must ensure that enough high-quality food is available to meet the needs of a continually growing population. Current and future agronomic prodn. of food, feed, fuel and fiber requires innovative solns. for existing and future challenges, such as climate change, resistance to pests, increased regulatory demands, renewable raw materials or requirements resulting from food chain partnerships. Modern agricultural chem. has to support farmers to manage these tasks. Today, the so-called 'side effects' of agrochems. regarding yield and quality are gaining more importance. Agrochem. companies with a strong research and development focus will have the opportunity to shape the future of agriculture by delivering innovative integrated solns. This review gives a comprehensive overview of the innovative products launched over the past 10 years and describes the progress of modern agricultural chem. and its future prospects. © 2015 Society of Chem. Industry.
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196
Goldberg, K.; Groombridge, S.; Hudson, J.; Leach, A. G.; MacFaul, P. A.; Pickup, A.; Poultney, R.; Scott, J. S.; Svensson, P. H.; Sweeney, J. Oxadiazole isomers: all bioisosteres are not created equal. MedChemComm 2012, 3, 600– 604, DOI: 10.1039/c2md20054f
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196
Oxadiazole isomers: all bioisosteres are not created equal
Goldberg, Kristin; Groombridge, Sam; Hudson, Julian; Leach, Andrew G.; MacFaul, Philip A.; Pickup, Adrian; Poultney, Ruth; Scott, James S.; Svensson, Per H.; Sweeney, Joseph
MedChemComm (2012), 3 (5), 600-604CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compds. were evaluated and found to have significant differences in their various phys. and pharmaceutical properties. Exptl. and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects.
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197
(a) Narjes, F.; Koehler, K. F.; Koch, U.; Gerlach, B.; Colarusso, S.; Steinkuhler, C.; Brunetti, M.; Altamura, S.; De Francesco, R.; Matassa, V. G. A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease. Bioorg. Med. Chem. Lett. 2002, 12, 701– 704, DOI: 10.1016/S0960-894X(01)00842-3
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197a
A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease
Narjes, Frank; Koehler, Konrad F.; Koch, Uwe; Gerlach, Benjamin; Colarusso, Stefania; Steinkuhler, Christian; Brunetti, Mirko; Altamura, Sergio; De Francesco, Raffaele; Matassa, Victor G.
Bioorganic & Medicinal Chemistry Letters (2002), 12 (4), 701-704CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
The difluoromethyl group was designed by computational chem. methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor AcAspGlu-NHCH(CHPH2)CO-Glu-NHCH(CH2C6H11)CONHCH(CH2CHF2)R (I, R = CHO) Ki 30 nM and reversible covalent inhibitors (I, R = CO2H) Ki 0.5 nM; and (I, R = COCO2H) Ki* 10 pM.
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(b) Di Marco, S.; Rizzi, M.; Volpari, C.; Walsh, M. A.; Narjes, F.; Colarusso, S.; De Francesco, R.; Matassa, V. G.; Sollazzo, M. J. Inhibition of the hepatitis C virus NS3/4A protease: the crystal structures of two protease-inhibitor complexes. J. Biol. Chem. 2000, 275, 7152– 7157, DOI: 10.1074/jbc.275.10.7152
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(c) Ontoria, J. M.; Di Marco, S.; Conte, I.; Di Francesco, M. E.; Gardelli, C.; Koch, U.; Matassa, V. G.; Poma, M.; Steinkühler, C.; Volpari, C.; Harper, S. The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease. J. Med. Chem. 2004, 47, 6443– 6446, DOI: 10.1021/jm049435d
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198
(a) Desiraju, G. R. The C-H···O hydrogen bond: structural implications and supramolecular design. Acc. Chem. Res. 1996, 29, 441– 449, DOI: 10.1021/ar950135n
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198a
The C-H···O Hydrogen Bond: Structural Implications and Supramolecular Design
Desiraju, Gautam R.
Accounts of Chemical Research (1996), 29 (9), 441-449CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review with 64 refs.
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(b) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl bioisostere: examining the “lipophilic hydrogen bond donor” concept. J. Med. Chem. 2017, 60, 797– 804, DOI: 10.1021/acs.jmedchem.6b01691
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198b
Difluoromethyl Bioisostere: Examining the "Lipophilic Hydrogen Bond Donor" Concept
Zafrani, Yossi; Yeffet, Dina; Sod-Moriah, Gali; Berliner, Anat; Amir, Dafna; Marciano, Daniele; Gershonov, Eytan; Saphier, Sigal
Journal of Medicinal Chemistry (2017), 60 (2), 797-804CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
There is a growing interest in org. compds. contg. the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepd. and their drug-like properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were detd. using Abraham's solute 1H NMR anal. The difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the exptl. Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ consts. These results may aid in the rational design of drugs contg. the difluoromethyl moiety.
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(c) Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J. CF₂H, a hydrogen bond donor. J. Am. Chem. Soc. 2017, 139, 9325– 9332, DOI: 10.1021/jacs.7b04457
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198c
CF2H, a Hydrogen Bond Donor
Sessler, Chanan D.; Rahm, Martin; Becker, Sabine; Goldberg, Jacob M.; Wang, Fang; Lippard, Stephen J.
Journal of the American Chemical Society (2017), 139 (27), 9325-9332CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The CF2H group, a potential surrogate for the OH group, can act as an unusual hydrogen bond donor, as confirmed ty crystallog., spectroscopic, and computational methods. Here, we demonstrate the bioisosterism of the OH and CF2H groups and the important roles of CF2-H···O hydrogen bonds in influencing intermol. interactions and conformational preferences. Exptl. evidence, corroborated by theory, reveals the distinctive nature of CF2H hydrogen bonding interactions relative to their normal OH hydrogen bonding counterparts.
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199
Zheng, Z. B.; D’Andrea, S. V.; Sun, L.-Q.; Wang, A. X.; Chen, Y.; Bowsher, M.; Hiebert, S.; Friborg, J.; Falk, P.; Hernandez, D.; Yu, F.; Sheaffer, A. K.; Zhai, G.; Knipe, J. O.; Mosure, K.; Rajamani, R.; Ng, A.; Gao, Q.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Sulfonamide inhibitors of hepatitis C virus NS3 protease bearing a novel P1 cyclopropyl difluoromethyl moiety. ACS Med. Chem. Lett., 2018, DOI : DOI: 10.1021/acsmedchemlett.7b00503
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200
Lin, C.-W.; Dutta, S.; Asatryan, A.; Chiu, Y.-L.; Wang, H.; Clifton, J., II; Campbell, A.; Liu, W. Pharmacokinetics, safety, and tolerability of single and multiple doses of ABT-493: a first-in-human study. J. Pharm. Sci. 2017, 106, 645– 651, DOI: 10.1016/j.xphs.2016.10.007
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201
Rodriguez-Torres, M.; Glass, S.; Hill, J.; Freilich, B.; Hassman, D.; Di Bisceglie, A. M.; Taylor, J. G.; Kirby, B. J.; Dvory-Sobol, H.; Yang, J. C.; An, D.; Stamm, L. M.; Brainard, D. M.; Kim, S.; Krefetz, D.; Smith, W.; Marbury, T.; Lawitz, E. GS-9857 in patients with chronic hepatitis C virus genotype 1–4 infection: a randomized, double-blind, dose-ranging phase 1 study. J. Viral Hepatitis 2016, 23, 614– 622, DOI: 10.1111/jvh.12527
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201
GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study
Rodriguez-Torres, M.; Glass, S.; Hill, J.; Freilich, B.; Hassman, D.; Di Bisceglie, A. M.; Taylor, J. G.; Kirby, B. J.; Dvory-Sobol, H.; Yang, J. C.; An, D.; Stamm, L. M.; Brainard, D. M.; Kim, S.; Krefetz, D.; Smith, W.; Marbury, T.; Lawitz, E.
Journal of Viral Hepatitis (2016), 23 (8), 614-622CODEN: JVHEER; ISSN:1365-2893. (John Wiley & Sons Ltd.)
Summary : GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-assocd. variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 lab. abnormalities were obsd. in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alk. phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median max. redns. in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was assocd. with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.
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202
(a) Xu, Y.; Prestwich, G. D. Concise synthesis of acyl migration-blocked 1,1-difluorinated analogues of lysophosphatidic acid. J. Org. Chem. 2002, 67, 7158– 7161, DOI: 10.1021/jo0203037
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202a
Concise Synthesis of Acyl Migration-Blocked 1,1-Difluorinated Analogs of Lysophosphatidic Acid
Xu, Yong; Prestwich, Glenn D.
Journal of Organic Chemistry (2002), 67 (20), 7158-7161CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) is an important phospholipid mediator produced by activated platelets and by ovarian cancer cells. Efforts to understand LPA signaling through G-protein-coupled receptors are hampered by the facile acyl migration that results in equilibration to a mixt. of the 1- or 2-acyl species under physiol. conditions. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogs from D-mannitol 1,2:5,6-bis-acetonide to give two 1,1-difluorodeoxy analogs of (2R)-acyl-sn-glycerol 3-phosphate. These compds. are migration-blocked analogs of the labile sn-2 LPA species. The 19F NMR of diastereotopic fluorines of the difluoromethyl group shows an unexpected solvent dependence.
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(b) Xu, Y.; Qian, L.; Pontsler, A. V.; McIntyre, T. M.; Prestwich, G. D. Synthesis of difluoromethyl substituted lysophosphatidic acid analogues. Tetrahedron 2004, 60, 43– 49, DOI: 10.1016/j.tet.2003.11.001
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202b
Synthesis of difluoromethyl substituted lysophosphatidic acid analogues
Xu, Yong; Qian, Lian; Pontsler, Aaron V.; McIntyre, Thomas M.; Prestwich, Glenn D.
Tetrahedron (2004), 60 (1), 43-49CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)
Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biol. that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with nuclear hormone receptor PPARγ. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogs from (S)-1,2,4-butanetriol to give two 3-difluoromethyl substituted analogs of 2-acyl-sn-glycerol 3-phosphate. These compds. are migration-blocked analogs of the liable sn-2 LPA species. Preliminary studies were conducted on a nuclear reporter assay in which monocytic cells were transfected with a luciferase construct activated by a PPARγ nuclear receptor response element and have shown that the 3-difluoromethyl substituted analogs are fully active as natural LPA.
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203
(a) Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Suresh, M. R.; Knaus, E. E. Synthesis of celecoxib analogues possessing an N-difluoromethyl-1,2-dihydropyrid-2-one 5-lipoxygenase pharmacophore: biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. J. Med. Chem. 2009, 52, 1525– 1529, DOI: 10.1021/jm8015188
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(b) Yu, G.; Praveen Rao, P. N.; Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Velázquez, C. A.; Suresh, M. R.; Knaus, E. E. Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual Inhibitors of cyclooxygenases and 5-lipoxygenase. Bioorg. Med. Chem. Lett. 2010, 20, 2168– 2173, DOI: 10.1016/j.bmcl.2010.02.040
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203b
Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual inhibitors of cyclooxygenases and 5-lipoxygenase
Yu, Gang; Praveen Rao, P. N.; Chowdhury, Morshed A.; Abdellatif, Khaled R. A.; Dong, Ying; Das, Dipankar; Velazquez, Carlos A.; Suresh, Mavanur R.; Knaus, Edward E.
Bioorganic & Medicinal Chemistry Letters (2010), 20 (7), 2168-2173CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
A new group of acetic acid and propionic acid regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compds. exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isoenzyme. Attachment of the N-difluoromethyl-1,2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, i.e., absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl)acetic acid (I) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Mol. modeling (docking) studies showed that the highly electroneg. CHF2 substituent present in I, that showed a modest selectivity for the COX-2 isoenzyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO2NH2) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region contg. the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5-LOX inhibitory drugs.
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204
Romanenko, V. D.; Kukhar, V. P. Fluorinated phosphonates: synthesis and biomedical application. Chem. Rev. 2006, 106, 3868– 3935, DOI: 10.1021/cr051000q
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204
Fluorinated Phosphonates: Synthesis and Biomedical Application
Romanenko, Vadim D.; Kukhar, Valery P.
Chemical Reviews (Washington, DC, United States) (2006), 106 (9), 3868-3935CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. The synthesis, fundamental chem. properties, and biomedical uses of the phosphonic acid derivs. that bear at least one F substituent on the organyl moiety are the subject of this review, which is organized as follows. The 1st part is a survey of synthetic methods used for the prepn. of fluorinated phosphonates. The 2nd part consists of a presentation of the different types of fluorophosphonates having significant biol. importance. The 3rd part describes the use of fluorinated phosphonates in biomedical studies (e.g. enzyme inhibitors, catalytic antibodies, antiviral agents, antitumor agents, anti-platelet-aggregation agents). Discussion of basic aspects of phosphonate and organofluorine chem. is reduced to min. to avoid redundancy to the long series of papers already published in journals and books. Also no particular attention will be paid to subjects that have recently been reviewed. In such cases, only the most important trends are briefly summarized. Literature coverage for the review extends up to Apr. 2006.
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205
(a) Blackburn, G. M.; Kent, D. E. A novel synthesis of R- and γ-fluoroalkylphosphonates. J. Chem. Soc., Chem. Commun. 1981, 511– 513, DOI: 10.1039/C39810000511
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(a) Chambers, R. D.; O’Hagan, D.; Lamont, R. B.; Jaina, S. C. The difluoromethylenephosphonate moiety as a phosphate mimic: X-ray structure of 2-amino-1,1,-difluoroethylphosphonic acid. J. Chem. Soc., Chem. Commun. 1990, 1053– 1054, DOI: 10.1039/c39900001053
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Some influences of fluorine in bioorganic chemistry
O'Hagan, David; Rzepa, Henry S.
Chemical Communications (Cambridge) (1997), (7), 645-652CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
A review with 76 refs. The stereochem. outcome on processing fluorinated substrate analogs by enzymes can often be controlled by electronic and stereoelectronic factors assocd. with the fluorine atoms. Interpreting or predicting the behavior of fluorinated compds. is complex and has led to the term flustrates (fluorine-contg. substrates) being coined. However, a greater appreciation of the electronic and stereoelectronic properties of org. fluorine renders the behavior of these compds. more interpretable.
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(d) Thatcher, G. R. J.; Campbell, A. S. Phosphonates as mimics of phosphate biomolecules: Ab initio calculations on tetrahedral ground states and pentacoordinate intermediates for phosphoryl transfer. J. Org. Chem. 1993, 58, 2272– 2281, DOI: 10.1021/jo00060a050
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Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T. New prospects toward the synthesis of difluoromethylated phosphate mimics. Chem. - Eur. J. 2016, 22, 10284– 10293, DOI: 10.1002/chem.201601310
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New Prospects toward the Synthesis of Difluomethylated Phosphate Mimics
Ivanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, Thomas
Chemistry - A European Journal (2016), 22 (30), 10284-10293CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review of the prepn., reactions and biolical activities of difluoromethylated phosphonate-contg. mols. The difluoromethyl phosphonate motif plays a crucial role in the development of bioactive mols. as it is considered as a phosphate bioisoster. Since 2010, a renewal of interest to enlarge the panel of reactions to access these difluoromethylated phosphonate-contg. mols. was witnessed. This Concept article charts the recent progress that was made.
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(a) Bialy, L.; Waldmann, H. Inhibitors of protein tyrosine phosphatases: next-generation drugs?. Angew. Chem., Int. Ed. 2005, 44, 3814– 3839, DOI: 10.1002/anie.200461517
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Inhibitors of protein tyrosine phosphatases: Next-generation drugs?
Bialy, Laurent; Waldmann, Herbert
Angewandte Chemie, International Edition (2005), 44 (25), 3814-3839CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The protein tyrosine phosphatases (PTPs) constitute a family of closely related key regulatory enzymes that dephosphorylate phosphotyrosine residues in their protein substrates. Malfunctions in PTP activity are linked to various diseases, ranging from cancer to neurol. disorders and diabetes. Consequently, PTPs have emerged as promising targets for therapeutic intervention in recent years. In this review, general aspects of PTPs and the development of small-mol. inhibitors of PTPs by both academic research groups and pharmaceutical companies are discussed. Different strategies have been successfully applied to identify potent and selective inhibitors. These studies constitute the basis for the future development of PTP inhibitors as drugs.
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(b) Combs, A. P. Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer. J. Med. Chem. 2010, 53, 2333– 2344, DOI: 10.1021/jm901090b
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208b
Recent Advances in the Discovery of Competitive Protein Tyrosine Phosphatase 1B Inhibitors for the Treatment of Diabetes, Obesity, and Cancer
Combs, Andrew P.
Journal of Medicinal Chemistry (2010), 53 (6), 2333-2344CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review.
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209
(a) Smyth, M. S.; Ford, H., Jr.; Burke, T. R., Jr. A general method for the preparation of benzylic R,R-difluorophosphonic acids; nonhydrolyzable mimetics of phosphotyrosine. Tetrahedron Lett. 1992, 33, 4137– 4140, DOI: 10.1016/S0040-4039(00)74672-7
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(b) Ivanova, M. V.; Bayle, A.; Besset, T.; Poisson, T.; Pannecoucke, X. Copper-mediated formation of aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates: a general approach to fluorinated phosphate mimics. Angew. Chem., Int. Ed. 2015, 54, 13406– 13410, DOI: 10.1002/anie.201507130
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209b
Copper-Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl Difluoromethylphosphonates: A General Approach to Fluorinated Phosphate Mimics
Ivanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Poisson, Thomas; Pannecoucke, Xavier
Angewandte Chemie, International Edition (2015), 54 (45), 13406-13410CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A general and efficient access to aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates is described. The developed methodol. using TMSCF2PO(OEt)2, iodonium salts and a Cu salt provided a straightforward manifold to reach these highly relevant products. The reaction proved to be highly functional group tolerant and proceeded under mild conditions, giving the corresponding products in good to excellent yields. This method represents the 1st general synthetic route to this important class of fluorinated scaffolds, which are well-recognized as in vivo stable phosphate surrogates.
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(c) Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T. Copper-mediated introduction of the CF₂PO(OEt)₂ motif: scope and limitations. Chem. - Eur. J. 2017, 23, 17318– 17338, DOI: 10.1002/chem.201703542
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209c
Copper-Mediated Introduction of the CF2PO(OEt)2 Motif: Scope and Limitations
Ivanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, Thomas
Chemistry - A European Journal (2017), 23 (68), 17318-17338CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Herein, a general procedure to access CF2PO(OEt)2-contg. mols. is reported. The reagent CuCF2PO(OEt)2 is accessible by a simple protocol and a broad range of substrates can be functionalized. The procedure allows the conversion of aryl diazonium salts, as well as aryl, heteroaryl, vinyl and alkynyl iodonium salts, into the corresponding fluorinated mols. at room temp. Mechanistic studies were performed to gain a better understanding of the reaction pathway. Under similar conditions, vinyl and aryl iodides, allyl halides, and benzyl bromides were also functionalized, and the scope and limitations of the reaction were studied. Finally, the procedure was extended to disulfides to offer new access to SCF2PO(OEt)2-contg. mols.
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210
(a) Panigrahi, K.; Eggen, M.; Maeng, J.-H.; Shen, Q.; Berkowitz, D. B. The α,α-difluorinated phosphonate L-pSer-analogue: an accessible chemical tool for studying kinase-dependent signal transduction. Chem. Biol. 2009, 16, 928– 936, DOI: 10.1016/j.chembiol.2009.08.008
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210a
The α,α-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase- Dependent Signal Transduction
Panigrahi, Kaushik; Eggen, MariJean; Maeng, Jun-Ho; Shen, Quanrong; Berkowitz, David B.
Chemistry & Biology (Cambridge, MA, United States) (2009), 16 (9), 928-936CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
A review. This overview focuses on the (α,α-difluoromethylene)phosphonate mimic of phosphoserine (pCF2Ser) and its application to the study of kinase-mediated signal transduction-pathways of great interest to drug development. The most versatile modes of access to these chem. biol. tools are discussed, organized by method of PCF2-C bond formation. The pCF2-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a "constitutive phosphorylation" phenotype and is seen to support native protein-protein interactions that depend on serine phosphorylation. Signal transduction pathways studied with this chem. biol. approach include the regulation of p53 tumor suppressor protein activity and of melatonin prodn. Given these successes, the future is bright for the use of such "teflon phospho-amino acid mimics" to map kinase-based signaling pathways.
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(b) Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a phosphoserine mimetic prodrug with potent 14–3-3 protein inhibitory activity. Chem. Biol. 2012, 19, 764– 771, DOI: 10.1016/j.chembiol.2012.05.011
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210b
Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity
Arrendale, Allison; Kim, Keunho; Choi, Jun Young; Li, Wei; Geahlen, Robert L.; Borch, Richard F.
Chemistry & Biology (Oxford, United Kingdom) (2012), 19 (6), 764-771CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)
Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs contg. phosphorylated serine and threonine residues. To create small mols. that inhibit such interactions, we developed methodol. for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small mol. inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylenephosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concns. when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concn.-dependent manner that correlates well with its ability to inhibit cell growth. This methodol. can be applied to target a variety of proteins contg. phosphoserine and other phosphoamino acid binding domains.
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211
(a) Rye, C. S.; Baell, J. B. Phosphate isosteres in medicinal chemistry. Curr. Med. Chem. 2005, 12, 3127– 3141, DOI: 10.2174/092986705774933452
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211a
Phosphate isosteres in medicinal chemistry
Rye, C. S.; Baell, J. B.
Current Medicinal Chemistry (2005), 12 (26), 3127-3141CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)
A review. The phosphate group is at the heart of an enormous no. of biol. processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biol. activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognize the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chem. research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognizing domains such as Src homol. 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilization of the phosphate moiety as part of an inhibitor is severely limited by the enzymic lability and poor cellular bioavailability of this highly charged recognition element. The development of phosphate isosteres attempts to address these issues by introducing a non-scissile bond and utilizing groups with less charge that are still able to interact favorably with the target protein in much the same way as the phosphate group does. Many phosphate mimics retain the phosphorus atom such as in the highly successful fluoromethylene phosphonates, whereas others have lost the tetrahedral phosphate geometry and are based on the combination of one or more carboxylate groups that generally reduce the overall charge of the mol. This review focuses on the recent developments and the use of phosphate isosteres in medicinal chem., covering roughly the past four years.
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(b) Elliott, T. S.; Slowey, A.; Ye, Y.; Conway, S. J. The use of phosphate bioisosteres in medicinal chemistry and chemical biology. MedChemComm 2012, 3, 735– 751, DOI: 10.1039/c2md20079a
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The use of phosphate bioisosteres in medicinal chemistry and chemical biology
Elliott, Thomas S.; Slowey, Aine; Ye, Yulin; Conway, Stuart J.
MedChemComm (2012), 3 (7), 735-751CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
A review. Phosphate and pyrophosphate groups play a central role in cellular signalling and consequently are of great interest to both medicinal chemists and chem. biologists. However, the design of mols. that can interfere with phosphate-based processes is recognized as a significant challenge, esp. when the resulting compds. must show good cellular penetration and stability. Herein, we have reviewed the full range of phosphate bioisosteres currently reported and provided the context of their deployment. We aim to provide a useful ref. for medicinal chemists and chem. biologists who are engaged in the design of mols. that target phosphate-binding proteins.
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(c) Zhang, Y.; Borrel, A.; Ghemtio, L.; Regad, L.; Boije af Gennäs, G.; Camproux, A.-C.; Yli-Kauhaluoma, J.; Xhaard, H. Structural isosteres of phosphate groups in the protein data bank. J. Chem. Inf. Model. 2017, 57, 499– 516, DOI: 10.1021/acs.jcim.6b00519
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211c
Structural Isosteres of Phosphate Groups in the Protein Data Bank
Zhang, Yuezhou; Borrel, Alexandre; Ghemtio, Leo; Regad, Leslie; Boije af Gennas, Gustav; Camproux, Anne-Claude; Yli-Kauhaluoma, Jari; Xhaard, Henri
Journal of Chemical Information and Modeling (2017), 57 (3), 499-516CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
We developed a computational workflow to mine the Protein Data Bank (PDB) for isosteric replacements that exist in different binding site environments but have not necessarily been identified and exploited in compd. design. Taking phosphate groups as examples, the workflow was used to construct 157 datasets, each composed of a ref. protein complexed with AMP, ADP, ATP, or pyrophosphate as well other ligands. Phosphate binding sites appeared to have a high hydration content and large size, resulting in U-shaped bioactive conformations recurrently found across unrelated protein families. A total of 16,413 replacements were extd., filtered for a significant structural overlap on phosphate groups, and sorted according to their SMILES codes. In addn. to the classical isosteres of phosphate, such as carboxylate, sulfone or sulfonamide, unexpected replacements that did not conserve charge or polarity, such as aryl, aliph., or pos. charged groups, were found.
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212
Dufresne, C.; Roy, P.; Wang, Z.; Asante-Appiah, E.; Cromlish, W.; Boie, Y.; Forghani, F.; Desmarais, S.; Wang, Q.; Skorey, K.; Waddleton, D.; Ramachandran, C.; Kennedy, B. P.; Xu, L.; Gordon, R.; Chan, C. C.; Leblanc, Y. The development of potent non-peptidic PTP-1B inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 1039– 1042, DOI: 10.1016/j.bmcl.2003.11.048
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Bahta, M.; Lountos, G. T.; Dyas, B.; Kim, S.-E.; Ulrich, R. G.; Waugh, D. S.; Burke, T. R., Jr. Utilization of nitrophenylphosphates and oxime-based ligation for the development of nanomolar affinity inhibitors of the Yersinia pestis outer protein H (YopH) phosphatase. J. Med. Chem. 2011, 54, 2933– 2943, DOI: 10.1021/jm200022g
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Morlacchi, P.; Mandal, P. K.; McMurray, J. S. Synthesis and in vitro evaluation of a peptidomimetic inhibitor targeting the Src homology 2 (SH2) domain of STAT6. ACS Med. Chem. Lett. 2014, 5, 69– 72, DOI: 10.1021/ml4003919
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Hakogi, T.; Yamamoto, T.; Fujii, S.; Ikeda, K.; Katsumura, S. Synthesis of sphingomyelin difluoromethylene analogue. Tetrahedron Lett. 2006, 47, 2627– 2630, DOI: 10.1016/j.tetlet.2006.02.018
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Synthesis of sphingomyelin difluoromethylene analog
Hakogi, Toshikazu; Yamamoto, Tetsuya; Fujii, Shinobu; Ikeda, Kiyoshi; Katsumura, Shigeo
Tetrahedron Letters (2006), 47 (15), 2627-2630CODEN: TELEAY; ISSN:0040-4039. (Elsevier B.V.)
As a new sphingomyelinase inhibitor, a novel sphingomyelin CF2 analog was designed and synthesized. One key step of this synthesis is the very mild hydrolysis of the oxazolidinone ring of methylphosphonate I, a suitable intermediate for the introduction of a di-Et difluoro-methylphosphonate group, by utilizing the characteristic electron withdrawing nature of the group at the oxazolidinone ring in an alc. solvent to produce the corresponding carbonate attaching at the secondary hydroxy group. The synthesized CF2 analog inactivated toward B. cereus sphingomyelinase with nearly the same attitude as the nitrogen analog that we previously reported.
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216
(a) Lapierre, J.; Ahmed, V.; Chen, M.-J.; Ispahany, M.; Guillemette, J. G.; Taylor, S. D. The difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 151– 155, DOI: 10.1016/j.bmcl.2003.09.089
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216a
The difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitors
Lapierre, Jennifer; Ahmed, Vanessa; Chen, Mei-Jin; Ispahany, Mehdi; Guillemette, J. Guy; Taylor, Scott D.
Bioorganic & Medicinal Chemistry Letters (2004), 14 (1), 151-155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)
Several estrone sulfate and estradiol sulfate analogs, in which the sulfate group was replaced with an α,α-difluoromethylenesulfonate group or an α,α-difluoromethylenetetrazole group, were examd. as inhibitors of steroid sulfatase (STS). These compds. were 4.5-10.5 times more potent than their non-fluorinated analogs. Moreover, the presence of the fluorines changed the mode of inhibition from mixed to competitive. The inhibitor bearing the α,α-difluoromethylenetetrazole group exhibited an affinity for STS approaching that of the natural STS substrate, estrone sulfate. Possible reasons for the enhanced affinity of the fluorinated compds. compared to their non-fluorinated counterparts are discussed.
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(b) Liu, Y.; Ahmed, V.; Hill, B.; Taylor, S. D. Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitor. Org. Biomol. Chem. 2005, 3, 3329– 3335, DOI: 10.1039/b508852f
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216b
Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitor
Liu, Yong; Ahmed, Vanessa; Hill, Bryan; Taylor, Scott D.
Organic & Biomolecular Chemistry (2005), 3 (18), 3329-3335CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
Steroid sulfatase (STS) catalyzes the hydrolysis of steroidal sulfates such as estrone sulfate (ES1) and is considered to be an attractive target in the treatment of steroid dependent cancers. A non-hydrolyzable estrone sulfate (ES1) analog bearing an α,α-difluorosulfonamide moiety at the 3-position on the A-ring, I, was synthesized. Key to the success of this synthesis was the first use of the allyl group as a sulfonamide protecting group. The pKa of this ES1 mimic in 0.1 M bis-tris propane, 10% DMSO was detd. to be 8.05 using 19F NMR. I is a reversible inhibitor with a Ki similar to that of its sulfonate analog at pH 7.0. It is more potent than its nonfluorinated sulfonamide analog and, its inhibitory potency increases with increasing pH, a trend opposite to that of other STS inhibitors. Possible reasons for this are presented.
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217
(a) Maltais, R.; Poirier, D. Steroid sulfatase inhibitors: a review covering the promising 2000–2010 decade. Steroids 2011, 76, 929– 948, DOI: 10.1016/j.steroids.2011.03.010
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(b) Mostafa, Y. A.; Taylor, S. D. Steroid derivatives as inhibitors of steroid sulfatase. J. Steroid Biochem. Mol. Biol. 2013, 137, 183– 198, DOI: 10.1016/j.jsbmb.2013.01.013
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Steroid derivatives as inhibitors of steroid sulfatase
Mostafa, Yaser A.; Taylor, Scott D.
Journal of Steroid Biochemistry and Molecular Biology (2013), 137 (), 183-198CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)
A review. Sulfated steroids function as a storage reservoir of biol. active steroid hormones. The sulfated steroids themselves are biol. inactive and only become active in vivo when they are converted into their desulfated (unconjugated) form by the enzyme steroid sulfatase (STS). Inhibitors of STS are considered to be potential therapeutics for the treatment of steroid-dependent cancers such as breast, prostate and endometrial cancer. The present review summarizes steroid derivs. as inhibitors of STS covering the literature from the early years of STS inhibitor development to Oct. of 2012. A brief discussion of the function, structure and mechanism of STS and its role in estrogen receptor-pos. (ER+) hormone-dependent breast cancer is also presented.This article is part of a Special Issue entitled "Synthesis and biol. testing of steroid derivs. as inhibitors".
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218
Kotoris, C. K.; Chen, M.-J.; Taylor, S. D. Novel phosphate mimetics for the design of non-peptidyl inhibitors of protein tyrosine phosphatases. Bioorg. Med. Chem. Lett. 1998, 8, 3275– 3280, DOI: 10.1016/S0960-894X(98)00598-8
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Lomelino, C.; McKenna, R. Carbonic anhydrase inhibitors: a review on the progress of patent literature (2011–2016). Expert Opin. Ther. Pat. 2016, 26, 947– 956, DOI: 10.1080/13543776.2016.1203904
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Carbonic anhydrase inhibitors: a review on the progress of patent literature (2011-2016)
Lomelino, Carrie; McKenna, Robert
Expert Opinion on Therapeutic Patents (2016), 26 (8), 947-956CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
Introduction: A large area of carbonic anhydrase (CA) research focuses on the inhibition of human CA IX and CA XII, as these isoforms have been designated as biomarkers and therapeutic targets for various cancer types. Areas covered: Recently, the majority of CA inhibitor (CAI) patents cover compd. design, synthesis, and delivery methods for the treatment of glaucoma and cancer. The anal. of included patents highlights the need for isoform specific inhibitors. This review covers the patents of medically relevant carbonic anhydrase inhibitors between 2011-2016. Expert opinion: The improvement of structure-based drug design methods and access to the crystal structures of human CA isoforms have improved inhibitor development. This progress can be obsd. in relation to the selective inhibition of CA IX for cancer treatments, with one inhibitor in clin. trials. However, the design of nonclassical CAIs is essential to further improve isoform specificity and prevent sulfur allergies.
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Blackburn, G. M.; Türkmen, H. Synthesis of α-fluoro- and α,α-difluoro-benzenemethanesulfonamides: new inhibitors of carbonic anhydrase. Org. Biomol. Chem. 2005, 3, 225– 226, DOI: 10.1039/B417327A
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Naim, M. J.; Alam, O.; Alam, M. J.; Alam, P.; Shrivastava, N. A review on pharmacological profile of morpholine derivatives. Int. J. Pharmacol. Pharm. Sci. 2015, 3, 40– 51
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Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059
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Predicting and tuning physicochemical properties in lead optimization: amine basicities
Morgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, Klaus
ChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
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Martin, R. E.; Plancq, B.; Gavelle, O.; Wagner, B.; Fischer, H.; Bendels, S.; Müller, K. Remote modulation of amine basicity by a phenylsulfone and a phenylthio group. ChemMedChem 2007, 2, 285– 287, DOI: 10.1002/cmdc.200600265
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Remote modulation of amine basicity by a phenylsulfone and a phenylthio group
Martin, Rainer E.; Plancq, Baptiste; Gavelle, Olivier; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Muller, Klaus
ChemMedChem (2007), 2 (3), 285-287CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
A series of Ph sulfones and phenylthioamines was studied with respect to their pKa values in water under std. conditions.
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Geneste, P.; Hugon, I.; Reminiac, C.; Lamaty, G.; Roque, J. P. The pK_a of substituted 4-piperidones. Bull. Soc. Chim. Fr. 1976, 5–6, 845– 846
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Huang, H.; Hutta, D. A.; Rinker, J. M.; Hu, H.; Parsons, W. H.; Schubert, C.; DesJarlais, R. L.; Crysler, C. S.; Chaikin, M. A.; Donatelli, R. R.; Chen, Y.; Cheng, D.; Zhou, Z.; Yurkow, E.; Manthey, C. L.; Player, M. R. Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors. J. Med. Chem. 2009, 52, 1081– 1099, DOI: 10.1021/jm801406h
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226
Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Goldsmith, P.; Haslam, C. P.; Mitchell, W. L.; Nicholson, N. H.; Page, L. W.; Patel, S.; Roomans, S.; Slingsby, B. P.; Swarbrick, M. E. Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB₂ agonists for the treatment of inflammatory pain. Bioorg. Med. Chem. Lett. 2010, 20, 465– 468, DOI: 10.1016/j.bmcl.2009.11.117
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Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory pain
Gleave, Robert J.; Beswick, Paul J.; Brown, Andrew J.; Giblin, Gerard M. P.; Goldsmith, Paul; Haslam, Carl P.; Mitchell, William L.; Nicholson, Neville H.; Page, Lee W.; Patel, Sadhana; Roomans, Susan; Slingsby, Brian P.; Swarbrick, Martin E.
Bioorganic & Medicinal Chemistry Letters (2010), 20 (2), 465-468CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
A series of 3-amino-6-aryl-pyridazines have been identified as CB2 agonists with high efficacy and selectivity against the CB1 receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analog I, a compd. with high potency in an in vivo model of inflammatory pain.
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(a) Sundar, B. G.; Bailey, T. R.; Dunn, D.; Hostetler, G. A.; Chatterjee, S.; Bacon, E. R.; Yue, C.; Schweizer, D.; Aimone, L. D.; Gruner, J. A.; Lyons, J.; Raddatz, R.; Lesur, B. Novel morpholine ketone analogs as potent histamine H₃ receptor inverse agonists with wake activity. Bioorg. Med. Chem. Lett. 2012, 22, 1546– 1549, DOI: 10.1016/j.bmcl.2012.01.004
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(b) Zulli, A.; Aimone, L. D.; Mathiasen, J. R.; Gruner, J. A.; Raddatz, R.; Bacon, E. R.; Hudkins, R. L. Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists. Bioorg. Med. Chem. Lett. 2012, 22, 2807– 2810, DOI: 10.1016/j.bmcl.2012.02.081
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Garton, N. S.; Barker, M. D.; Davis, R. P.; Douault, C.; Hooper-Greenhill, E.; Jones, E.; Lewis, H. D.; Liddle, J.; Lugo, D.; McCleary, S.; Preston, A. G. S.; Ramirez-Molina, C.; Neu, M.; Shipley, T. J.; Somers, D. O.; Watson, R. J.; Wilson, D. M. Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 4606– 4612, DOI: 10.1016/j.bmcl.2016.08.070
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Ahmad, S.; Washburn, W. N.; Hernandez, A. S.; Bisaha, S.; Ngu, K.; Wang, W.; Pelleymounter, M. A.; Longhi, D.; Flynn, N.; Azzara, A. V.; Rohrbach, K.; Devenny, J.; Rooney, S.; Thomas, M.; Glick, S.; Godonis, H.; Harvey, S.; Zhang, H.; Gemzik, B.; Janovitz, E. B.; Huang, C.; Zhang, L.; Robl, J. A.; Murphy, B. J. Synthesis and antiobesity properties of 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): a highly efficacious melanin concentrating hormone receptor 1 (MCHR1) inhibitor. J. Med. Chem. 2016, 59, 8848– 8858, DOI: 10.1021/acs.jmedchem.6b00676
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(a) Deliencourt-Godefroy, G.; Lopes, L. Family of Aryl, Heteroaryl, O-Aryl and O-Heteroaryl Carbasugars. World Patent Application WO 2012/160218, Nov. 29, 2012.
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(a) Berry, C. B.; Bubser, M.; Jones, C. K.; Hayes, J. P.; Wepy, J. A.; Locuson, C. W.; Daniels, J. S.; Lindsley, C. W.; Hopkins, C. R. Discovery and characterization of ML398, a potent and selective antagonist of the D₄ receptor with in vivo activity. ACS Med. Chem. Lett. 2014, 5, 1060– 1064, DOI: 10.1021/ml500267c
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(b) Witt, J. O.; McCollum, A. L.; Hurtado, M. A.; Huseman, E. D.; Jeffries, D. E.; Temple, K. J.; Plumley, H. C.; Blobaum, A. L.; Lindsley, C. W.; Hopkins, C. R. Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D₄R) antagonists. Bioorg. Med. Chem. Lett. 2016, 26, 2481– 2488, DOI: 10.1016/j.bmcl.2016.03.102
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Saurat, T.; Buron, F.; Rodrigues, N.; de Tauzia, M.-L.; Colliandre, L.; Bourg, S.; Bonnet, P.; Guillaumet, G.; Akssira, M.; Corlu, A.; Guillouzo, C.; Berthier, P.; Rio, P.; Jourdan, M.-L.; Bénédetti, H.; Routier, S. Design, synthesis, and biological activity of pyridopyrimidine scaffolds as novel PI3K/mTOR dual inhibitors. J. Med. Chem. 2014, 57, 613– 631, DOI: 10.1021/jm401138v
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Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Direct synthesis of fluorinated heteroarylether bioisosteres. Angew. Chem., Int. Ed. 2013, 52, 3949– 3952, DOI: 10.1002/anie.201300763
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Direct Synthesis of Fluorinated Heteroarylether Bioisosteres
Zhou, Qianghui; Ruffoni, Alessandro; Gianatassio, Ryan; Fujiwara, Yuta; Sella, Eran; Shabat, Doron; Baran, Phil S.
Angewandte Chemie, International Edition (2013), 52 (14), 3949-3952CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A modular synthesis of reagents (e.g. sodium 1,1-difluoroethylsulfinate) that can be used for direct incorporation of 1,1-difluoroalkyl groups onto various heterocycles is reported. The scope and generality of the incorporation of difluoroalkyl groups is exemplified with the 1,1-difluoroethyl group, and a proof of principle is shown for a general synthesis of fluorinated heteroaryl ether bioisosteres.
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Xue, F.; Li, H.; Delker, S. L.; Fang, J.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Potent, Highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase. J. Am. Chem. Soc. 2010, 132, 14229– 14238, DOI: 10.1021/ja106175q
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234
Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase
Xue, Fengtian; Li, Huiying; Delker, Silvia L.; Fang, Jianguo; Martasek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.
Journal of the American Chemical Society (2010), 132 (40), 14229-14238CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compds., e.g., I, contg. a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compds., (S,S) vs. (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF2 moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compds. with monocationic character under physiol. pH conditions. Biol. evaluations have led to a nNOS inhibitor with a Ki of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calcns. indicated that the low pKa NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compd. to the parent mol. shows 22% for the difluorinated compd. vs. essentially no oral bioavailability for the parent compd. This indicates that the goal of this research to make compds. with only one protonated nitrogen atom at physiol. pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.
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Anderson, M. O.; Zhang, J.; Liu, Y.; Yao, C.; Phuan, P.-W.; Verkman, A. S. Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B. J. Med. Chem. 2012, 55, 5942– 5950, DOI: 10.1021/jm300491y
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235
Nanomolar Potency and Metabolically Stable Inhibitors of Kidney Urea Transporter UT-B
Anderson, Marc O.; Zhang, Jicheng; Liu, Yan; Yao, Chenjuan; Phuan, Puay-Wah; Verkman, A. S.
Journal of Medicinal Chemistry (2012), 55 (12), 5942-5950CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Urea transporters, which include UT-B in kidney microvessels, are potential targets for development of drugs with a novel diuretic ('urearetic') mechanism. We recently identified, by high-throughput screening, a triazolothienopyrimidine UT-B inhibitor, 1, that selectively and reversibly inhibited urea transport with IC50 = 25.1 nM and reduced urinary concn. in mice (Yao et al. J. Am. Soc. Nephrol., in press). Here, we analyzed com. available analogs of (I) to establish a structure-activity series and synthesized a targeted library of 11 analogs to identify potent, metabolically stable UT-B inhibitors. The best compd., {3-[4-(1,1-difluoroethyl)benzenesulfonyl]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}thiophen-2-ylmethylamine, (II), had IC50 of 23 and 15 nM for inhibition of urea transport by mouse and human UT-B, resp., and ∼40-fold improved in vitro metabolic stability compared to I. In mice, II accumulated in kidney and urine and reduced max. urinary concn. Triazolothienopyrimidine may be useful for therapy of diuretic-refractory edema in heart and liver failure.
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Piotrowski, D. W.; Futatsugi, K.; Warmus, J. S.; Orr, S. T.M.; Freeman-Cook, K. D.; Londregan, A. T.; Wei, L.; Jennings, S. M.; Herr, M.; Coffey, S. B.; Jiao, W.; Storer, G.; Hepworth, D.; Wang, J.; Lavergne, S. Y.; Chin, J. E.; Hadcock, J. R.; Brenner, M. B.; Wolford, A. C.; Janssen, A. M.; Roush, N. S.; Buxton, J.; Hinchey, T.; Kalgutkar, A. S.; Sharma, R.; Flynn, D. A. Identification of tetrahydropyrido[4,3-d]pyrimidine amides as a new class of orally bioavailable TGR5 agonists. ACS Med. Chem. Lett. 2013, 4, 63– 68, DOI: 10.1021/ml300277t
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236
Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists
Piotrowski, David W.; Futatsugi, Kentaro; Warmus, Joseph S.; Orr, Suvi T. M.; Freeman-Cook, Kevin D.; Londregan, Allyn T.; Wei, Liuqing; Jennings, Sandra M.; Herr, Michael; Coffey, Steven B.; Jiao, Wenhua; Storer, Gregory; Hepworth, David; Wang, Jian; Lavergne, Sophie Y.; Chin, Janice E.; Hadcock, John R.; Brenner, Martin B.; Wolford, Angela C.; Janssen, Ann M.; Roush, Nicole S.; Buxton, Joanne; Hinchey, Terri; Kalgutkar, Amit S.; Sharma, Raman; Flynn, Declan A.
ACS Medicinal Chemistry Letters (2013), 4 (1), 63-68CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biol. target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of I, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that I could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5.
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(a) Xing, L.; Blakemore, D. C.; Narayanan, A.; Unwalla, R.; Lovering, F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. Fluorine in drug design: a case study with fluoroanisoles. ChemMedChem 2015, 10, 715– 726, DOI: 10.1002/cmdc.201402555
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237a
Fluorine in Drug Design: A Case Study with Fluoroanisoles
Xing, Li; Blakemore, David C.; Narayanan, Arjun; Unwalla, Ray; Lovering, Frank; Denny, R. Aldrin; Zhou, Huanyu; Bunnage, Mark E.
ChemMedChem (2015), 10 (4), 715-726CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
Anisole and fluoroanisoles display distinct conformational preferences, as evident from a survey of their crystal structures. In addn. to altering the free ligand conformation, various degrees of fluorination have a strong impact on physicochem. and pharmacokinetic properties. Anal. of anisole and fluoroanisole matched mol. pairs in the Pfizer corporate database reveals interesting trends: (1) PhOCF3 increases log D by ∼1 log unit over PhOCH3 compds.; (2) PhOCF3 shows lower passive permeability despite its higher lipophilicity; and (3) PhOCF3 does not appreciably improve metabolic stability over PhOCH3. Emerging from the investigation, difluoroanisole (PhOCF2H) strikes a better balance of properties with noticeable advantages of log D and transcellular permeability over PhOCF3. Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH3 with PhOCF3 is a common tactic to optimize ADME properties, the anal. suggests PhOCF2H may be a more attractive alternative, and greater exploitation of this motif is recommended.
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(b) Jeschke, P.; Baston, E.; Leroux, F. R. α-Fluorinated ethers as “exotic” entity in medicinal chemistry. Mini-Rev. Med. Chem. 2007, 7, 1027– 1034, DOI: 10.2174/138955707782110150
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α-Fluorinated ethers as "exotic" entity in medicinal chemistry
Jeschke, Peter; Baston, Eckhard; Leroux, Frederic R.
Mini-Reviews in Medicinal Chemistry (2007), 7 (10), 1027-1034CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)
A review. After nitrogen, fluorine occupies the position of second favorite heteroelement in life science-oriented research. In contrast, the trifluoromethoxy group is still perhaps the least well understood fluorine substituent, although its occurrence has significantly increased in the recent years. Today, significant application areas for trifluoromethoxy substituted pharmaceuticals are in the field of analgesics, anesthetics, cardiovascular drugs, respiratory drugs, psychopharmacol. drugs, neurol. drugs, gastrointestinal drugs and anti-infective therapeutics. The present review will give an overlook of its use in medicinal chem.
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238
(a) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis. J. Chem. Inf. Model. 2008, 48, 1– 24, DOI: 10.1021/ci7002494
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238a
Small molecule conformational preferences derived from crystal structure data. a medicinal chemistry focused analysis
Brameld, Ken A.; Kuhn, Bernd; Reuter, Deborah C.; Stahl, Martin
Journal of Chemical Information and Modeling (2008), 48 (1), 1-24CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
A review. Based on torsion angle distributions of frequently occurring substructures, conformation preferences of druglike mols. are presented, accompanied by a review of the relevant literature. First, the relevance of the Cambridge Structural Database (CSD) for drug design is demonstrated by comparing substructures present in compds. entering clin. trials with those found in the CSD and protein-bound ligands in the Protein Data Bank (PDB). Next, we briefly highlight preferred conformations of elementary acyclic systems, followed by a discussion of sulfonamide conformations. Due to their central role in medicinal chem., we discuss properties of aryl ring substituents in depth, including biaryl systems and systems of two aryl rings connected by two acyclic bonds. For a subset of torsion motifs, we also compare torsion angle histograms derived from CSD structures with those derived from ligands in the PDB. Furthermore, selected properties of some six- and seven-membered ring systems are discussed. The article closes with a section on attractive sulfur-oxygen contacts.
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(b) Hehre, W. J.; Radom, L.; Pople, J. A. Molecular orbital theory of the electronic structure of organic compounds. XII. Conformations, stabilities, and charge distributions in monosubstituted benzenes. J. Am. Chem. Soc. 1972, 94, 1496– 1504, DOI: 10.1021/ja00760a011
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238b
Molecular orbital theory of the electronic structure of organic compounds. XII. Conformations, stabilities, and charge distributions in monosubstituted benzenes
Hehre, Warren J.; Radom, Leo; Pople, John A.
Journal of the American Chemical Society (1972), 94 (5), 1496-504CODEN: JACSAT; ISSN:0002-7863.
Ab initio MO theory with the minimal Slater type orbital obtained by using 3 Gaussian functions basis set is used to study the conformations, stabilities, and charge distributions of 35 monosubstituted benzenes. Mol. conformations are detd. by conjugation effects, although steric interactions cause significant perturbations in some cases. Rotational barriers are a little higher than exptl. values. In the most stable forms of these mols., the Ph group is stabilizing compared with Me. On the other hand, a Ph group oriented perpendicular to the π system of the substituent (e.g., the orthogonal forms of PhNO2 and BzH) is often destabilizing. Calcd. dipole moments are consistently lower than exptl. values, but most exptl. trends are reproduced. Calcd. and exptl. mesomeric moments are in close agreement. Theoretical charge distributions support many of the ideas of classical org. chemistry. In addn. to the transfer of π electrons to or from the substituent into the aromatic ring, polarization of the π electrons within the ring is important. Charge distributions in orthogonal conformations can be strikingly different to those in corresponding planar forms.
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(c) Anderson, G. M.; Kollman, P. A.; Domelsmith, L. N.; Houk, K. N. Methoxy group nonplanarity in o-dimethoxybenzenes. Simple predictive models for conformations and rotational barriers in alkoxyaromatics. J. Am. Chem. Soc. 1979, 101, 2344– 2352, DOI: 10.1021/ja00503a018
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239
(a) Kapustin, E. G.; Bzhezovsky, V. M.; Yagupolskii, L. M. Torsion potentials and electronic structure of trifluoromethoxy- and trifluoromethylthiobenzene: an ab initio study. J. Fluorine Chem. 2002, 113, 227– 237, DOI: 10.1016/S0022-1139(01)00556-5
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Torsion potentials and electronic structure of trifluoromethoxy- and trifluoromethylthiobenzene: an ab initio study
Kapustin, Evgenij G.; Bzhezovsky, Vladimir M.; Yagupolskii, Lev M.
Journal of Fluorine Chemistry (2002), 113 (2), 227-237CODEN: JFLCAR; ISSN:0022-1139. (Elsevier Science B.V.)
Potential functions of internal rotation about the Csp2-X bonds in mols. PhXCF3 (X = O, S) were calcd. at the second-order Moller-Plesset perturbation level of theory with 6-31G(d) basis set. The profile of the potential function and the rotation barrier (ΔE=3.0 kJ/mol) found for PhOCF3 suggest that, depending on exptl. conditions, there can be either free rotation about the Csp2-O bond or the conformational equil. is shifted to the side of the orthogonal form. The rotational barrier for PhSCF3 is 14.7 kJ/mol and the mol. exists in the stable orthogonal conformation. The nature of hybridization, energy and population of lone electron pairs (LPs) on the O and S atoms were considered by using the Natural Bond Orbital (NBO) method. The energy of interactions of the LPs with antibonding π*-orbitals of the arom. moiety were estd. for different conformations. The distribution of electron d. in the mols. was discussed. The results were compared with analogous calcns. on the mols. PhXMe.
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(b) Horne, D. B.; Bartberger, M. D.; Kaller, M. R.; Monenschein, H.; Zhong, W.; Hitchcock, S. A. Synthesis and conformational analysis of α,α-difluoroalkyl heteroaryl ethers. Tetrahedron Lett. 2009, 50, 5452– 5455, DOI: 10.1016/j.tetlet.2009.07.060
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Hartz, R. A.; Ahuja, V. T.; Rafalski, M.; Schmitz, W. D.; Brenner, A. B.; Denhart, D. J.; Ditta, J. L.; Deskus, J. A.; Yue, E. W.; Arvanitis, A. G.; Lelas, S.; Li, Y.-W.; Molski, T. F.; Wong, H.; Grace, J. E.; Lentz, K. A.; Li, J.; Lodge, N. J.; Zaczek, R.; Combs, A. P.; Olson, R. E.; Mattson, R. J.; Bronson, J. J.; Macor, J. E. In vitro intrinsic clearance-based optimization of N³-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists. J. Med. Chem. 2009, 52, 4161– 4172, DOI: 10.1021/jm900302q
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240
In Vitro Intrinsic Clearance-Based Optimization of N3-Phenylpyrazinones as Corticotropin-Releasing Factor-1 (CRF1) Receptor Antagonists
Hartz, Richard A.; Ahuja, Vijay T.; Rafalski, Maria; Schmitz, William D.; Brenner, Allison B.; Denhart, Derek J.; Ditta, Jonathan L.; Deskus, Jeffrey A.; Yue, Eddy W.; Arvanitis, Argyrios G.; Lelas, Snjezana; Li, Yu-Wen; Molski, Thaddeus F.; Wong, Harvey; Grace, James E.; Lentz, Kimberley A.; Li, Jianqing; Lodge, Nicholas J.; Zaczek, Robert; Combs, Andrew P.; Olson, Richard E.; Mattson, Ronald J.; Bronson, Joanne J.; Macor, John E.
Journal of Medicinal Chemistry (2009), 52 (14), 4161-4172CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF1) receptor antagonists. Selected compds., e.g. I, proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, an in vitro intrinsic clearance-based approach is described to the optimization of pyrazinone-based CRF1 receptor antagonists wherein sites of metab. were identified by incubation with human liver microsomes. It was found that the rate of metab. could be decreased by incorporation of appropriate substituents at the primary sites of metab. This led to the discovery of I, a highly potent (IC50 = 1.0 nM) and selective CRF1 receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.
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241
(a) Massa, M. A.; Spangler, D. P.; Durley, R. C.; Hickory, B. S.; Connolly, D. T.; Witherbee, B.J.; Smith, M. E.; Sikorski, J. A. Novel heteroaryl replacements of aromatic 3-tetrafluoroethoxy substituents in trifluoro-3-(tertiaryamino)-2-propanols as potent inhibitors of cholesteryl ester transfer protein. Bioorg. Med. Chem. Lett. 2001, 11, 1625– 1628, DOI: 10.1016/S0960-894X(01)00244-X
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(b) Reinhard, E. J.; Wang, J. L.; Durley, R. C.; Fobian, Y. M.; Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.; Norton, M. B.; Promo, M. A.; Tollefson, M. B.; Vernier, W. F.; Connolly, D. T.; Witherbee, B. J.; Melton, M. A.; Regina, K. J.; Smith, M. E.; Sikorski, J. A. Discovery of a simple picomolar inhibitor of cholesteryl ester transfer protein. J. Med. Chem. 2003, 46, 2152– 2168, DOI: 10.1021/jm020528+
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241b
Discovery of a Simple Picomolar Inhibitor of Cholesteryl Ester Transfer Protein
Reinhard, Emily J.; Wang, Jane L.; Durley, Richard C.; Fobian, Yvette M.; Grapperhaus, Margaret L.; Hickory, Brian S.; Massa, Mark A.; Norton, Monica B.; Promo, Michele A.; Tollefson, Michael B.; Vernier, William F.; Connolly, Daniel T.; Witherbee, Bryan J.; Melton, Michele A.; Regina, Karen J.; Smith, Mark E.; Sikorski, James A.
Journal of Medicinal Chemistry (2003), 46 (11), 2152-2168CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead I, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compds. in which the phenoxy group was substituted at the 3, 4, or 5 positions. In general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency relative to I, while analogs contg. electron-donating or hydrogen bond accepting groups exhibited lower potency. Compds. with polar or strong electron-withdrawing groups also displayed lower potency. Replacement of the phenoxy ring in I with either simple aliph. or cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better compds., a representative series was prepd. as the chirally pure R(+) enantiomers, and from these, the 4-chloro-3-ethylphenoxy analog was identified as a potent inhibitor of CETP activity in buffer (IC50 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and biochem. characterization of the 4-chloro-3-ethylphenoxy analog are reported along with its preliminary pharmacol. assessment in animals.
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(c) Mantlo, N. B.; Escribano, A. Update on the discovery and development of cholesteryl ester transfer protein inhibitors for reducing residual cardiovascular risk. J. Med. Chem. 2014, 57, 1– 17, DOI: 10.1021/jm400574e
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241c
Update on the Discovery and Development of Cholesteryl Ester Transfer Protein Inhibitors for Reducing Residual Cardiovascular Risk
Mantlo, Nathan B.; Escribano, Ana
Journal of Medicinal Chemistry (2014), 57 (1), 1-17CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester and triglycerides between plasma lipoprotein particles HDL and LDL/VLDL, resulting in equilibration between these lipoprotein fractions. Therapy that modulates HDL metab. to increase HDL-c levels could be an effective strategy to reduce residual cardiovascular risk since it is estd. that for each mg/dL increase in plasma HDL cholesterol, there could be a 2-3% decrease in cardiovascular risk. Modification of the lipoprotein profile by CETP inhibitors is promising, but the beneficial effect of reducing coronary heart disease risk has not yet been proven. To date, four CETP inhibitors have advanced to phase 3 cardiovascular outcome clin. trials, and two have been terminated for off-target adverse effects and lack of efficacy. This perspective will summarize recent events, new research developments, and the discovery of new classes of CETP inhibitors.
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242
(a) Heinrich, T.; Böttcher, H.; Gericke, R.; Bartoszyk, G. D.; Anzali, S.; Seyfried, C. A.; Greiner, H. E.; van Amsterdam, C. Synthesis and structure-activity relationship in a class of indolebutylpiperazines as dual 5-HT_1A receptor agonists and serotonin reuptake inhibitors. J. Med. Chem. 2004, 47, 4684– 4692, DOI: 10.1021/jm040793q
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(b) Heinrich, T.; Böttcher, H.; Bartoszyk, G. D.; Schwartz, H.; Anzali, S.; März, J.; Greiner, H. E.; Seyfried, C. A. Bioisosterism of fluorine and cyano as indole substituents. Theoretical, in vitro and in vivo examination. Chimia 2004, 58, 143– 147, DOI: 10.2533/000942904777678118
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242b
Bioisosterism of fluorine and cyano as indole substituents. Theoretical, in vitro and in vivo examination
Heinrich, Timo; Boettcher, Henning; Bartoszyk, Gerd D.; Schwartz, Harry; Anzali, Soheila; Maerz, Joachim; Greiner, Hartmut E.; Seyfried, Christoph A.
Chimia (2004), 58 (3), 143-147CODEN: CHIMAD; ISSN:0009-4293. (Swiss Chemical Society)
A review. Fluorine substitution modifies structural attributes and often induces unexpected effects. When substituting fluorine with cyano in position 5 of the indole in indole-butyl-amines, the properties of the compds. proved to be very comparable. In vitro target-profile, metab., and in vivo activity in the ultrasonic vocalization test indicate bioisosterism between the two substituents.
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243
(a) Altomonte, S.; Zanda, M. Synthetic chemistry and biological activity of pentafluorosulphanyl (SF₅) organic molecules. J. Fluorine Chem. 2012, 143, 57– 93, DOI: 10.1016/j.jfluchem.2012.06.030
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243a
Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules
Altomonte, Stefano; Zanda, Matteo
Journal of Fluorine Chemistry (2012), 143 (), 57-93CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
A review. The pentafluorosulphanyl group (SF5) is a highly stable chem. function which has been attracting a great deal of interest owing to its peculiar chem., structural, physicochem. and biol. properties. Progress in the area of SF5-compds. has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF5-group into org. mols. However, recent synthetic progress, the availability of some SF5-building blocks from com. suppliers and the discovery of interesting properties of SF5-substituted mols. in materials science, biol. and drug discovery are giving new momentum to research in this fascinating area of fluorine chem. Synthesis, reactivity and biol. properties of SF5-substituted org. mols. are herein reviewed with an emphasis on the work published after year 2000.
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(b) Sowaileh, M. F.; Hazlitt, R. A.; Colby, D. A. Application of the pentafluorosulfanyl group as a bioisosteric replacement. ChemMedChem 2017, 12, 1481– 1490, DOI: 10.1002/cmdc.201700356
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243b
Application of the Pentafluorosulfanyl Group as a Bioisosteric Replacement
Sowaileh, Munia F.; Hazlitt, Robert A.; Colby, David A.
ChemMedChem (2017), 12 (18), 1481-1490CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
The success of fluorinated mols. in drug design has led medicinal chemists to search for new fluorine-contg. substituents. A major recently developed group is the pentafluorosulfanyl group. This group is stable under physiol. conditions and displays unique phys. and chem. properties. There are currently few synthetic methods to install the SF5 group, yet efforts to integrate this group into lead optimization continue unabated. Typically, the SF5 group has been used as a replacement for trifluoromethyl, tert-Bu, halogen, or nitro groups. In this review, the use of the SF5 group as a bioisosteric replacement for each of these three functionalities is compared and contrasted across various groups of biol. active mols. The organization and presentation of these data should be instructive to medicinal chemists considering to design synthetic strategies to access SF5-substituted mols.
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244
(a) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.; Lien, E. J. Aromatic substituent constants for structure-activity correlations. J. Med. Chem. 1973, 16, 1207– 1216, DOI: 10.1021/jm00269a003
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244a
Aromatic substituent constants for structure-activity correlations
Hansch, Corwin; Leo, Albert; Unger, Stefan H.; Kim, Ki Hwai; Nikaitani, Donald; Lien, Eric J.
Journal of Medicinal Chemistry (1973), 16 (11), 1207-16CODEN: JMCMAR; ISSN:0022-2623.
The arom. substituent consts. π (lipophilic), σm and σp (electronic), and molar refractivity (steric) were collected from the literature for 236 substituents, including 128 π values and 191 values for which both σm and σp were found. The field and resonance electronic properties of C. G. Swain and E. C. Lupton (1968) were calcd. for these 191 substituents by a corrected procedure and were essentially orthogonal. The mutual correlation of σm and σp was high.
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(b) Hansch, C.; Leo, A.; Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 1991, 91, 165– 195, DOI: 10.1021/cr00002a004
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244b
A survey of Hammett substituent constants and resonance and field parameters
Hansch, Corwin; Leo, A.; Taft, R. W.
Chemical Reviews (Washington, DC, United States) (1991), 91 (2), 165-95CODEN: CHREAY; ISSN:0009-2665.
Included in this review is an anal. of newer methods which can supplant this classic procedure for detn. of the title consts., 283 refs.
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(c) Lien, E. J.; Guo, Z.-R.; Li, R.-L.; Su, C.-T. Use of dipole moment as a parameter in drug-receptor interaction and quantitative structure-activity relationship studies. J. Pharm. Sci. 1982, 71, 641– 655, DOI: 10.1002/jps.2600710611
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245
Du, J.; Hua, G.; Beier, P.; Slawin, A. M. Z.; Woollins, J. D. Single crystal X-ray structural features of aromatic compounds having a pentafluorosulfuranyl (SF₅) functional group. Struct. Chem. 2017, 28, 723– 733, DOI: 10.1007/s11224-016-0854-2
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245
Single crystal X-ray structural features of aromatic compounds having a pentafluorosulfuranyl (SF5) functional group
Du, Junyi; Hua, Guoxiong; Beier, Peter; Slawin, Alexandra M. Z.; Woollins, J. Derek
Structural Chemistry (2017), 28 (3), 723-733CODEN: STCHES; ISSN:1040-0400. (Springer)
Nine pentafluorosulfuranyl (SF5)-contg. arom. compds. have been characterized crystallog. The SF5 group has an umbrella geometry, and the sulfur atom in the SF5 group is in an approx. octahedral coordination environment. All S-F bond lengths [1.572(3)-1.618(3) Å] are very similar, and the C-S-Fax bond angles [178.94(14)-180°] are very close to each other. The angle of two adjacent Feq is approx. 90°. The intramol. and intermol. interactions such as Caryl-H···Feq, Caryl-H···O/N/F/Cl interactions, and π-stacking interactions play a very important role in their three-dimensional packing frameworks.
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246
Rouxel, C.; Le Droumaguet, C.; Macé, Y.; Clift, S.; Mongin, O.; Magnier, E.; Blanchard-Desce, M. Octupolar derivatives functionalized with superacceptor peripheral groups: synthesis and evaluation of the electron-withdrawing ability of potent unusual groups. Chem. - Eur. J. 2012, 18, 12487– 12497, DOI: 10.1002/chem.201103460
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246
Octupolar Derivatives Functionalized with Superacceptor Peripheral Groups: Synthesis and Evaluation of the Electron-Withdrawing Ability of Potent Unusual Groups
Rouxel, Cedric; Le Droumaguet, Celine; Mace, Yohan; Clift, Sophie; Mongin, Olivier; Magnier, Emmanuel; Blanchard-Desce, Mireille
Chemistry - A European Journal (2012), 18 (39), 12487-12497, S12487/1-S12487/6CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Novel tripodal derivs. with a triphenylamine core and that bear "superacidifiers" (i.e., fluorinated sulfoximinyl blocks) or novel sulfiliminyl moieties as peripheral groups were synthesized. These new chromophores show strong absorption in the near-UV region and emission in the visible region. The fluorinated sulfoximinyl moieties were found to behave as potent auxochromic and electron-withdrawing (EW) groups, thus leading to red shifted absorption and emission. These moieties promote a core-to-periphery intramol. charge transfer (ctp-ICT) transition, the energy of which was found to be correlated to their EW strength. In this study, we provide evidence of a linear correlation between the Hammett const. (σp) values and the electronic gap between the ground and first excited state of the three-branched derivs. This in turn was used to derive σp values of fluorinated sulfoximinyl moieties. These EWGs show unprecedentedly high σp values, up to 1.45 relative to 0.8 for NO2. Also, by using this method, the sulfiliminyl moiety was shown to exhibit similar EW strength as NO2, while promoting improved transparency and soly. Finally, the superior EW strength of the fluorinated sulfoximine peripheral moieties was shown to induce significant enhancement of the two-photon absorption responses in the red near-IR region of the three-branched derivs. relative to similar octupoles that bear more usual strong EW groups. These characteristics (improved nonlinear responses or transparency) open new routes for the design of nonlinear optical (NLO) chromophores for optical limiting or electro-optical modulation. Such building blocks could also be of interest for optoelectronic applications, including the development of solar cells.
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247
(a) Bowden, R. D.; Comina, P. J.; Greenhall, M. P.; Kariuki, B. M.; Loveday, A.; Philp, D. A new method for the synthesis of aromatic sulfurpentafluorides and studies of the stability of the sulfurpentafluoride group in common synthetic transformations. Tetrahedron 2000, 56, 3399– 3408, DOI: 10.1016/S0040-4020(00)00184-8
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(b) Savoie, P. R.; Welch, J. T. Preparation and utility of organic pentafluorosulfanyl-containing compounds. Chem. Rev. 2015, 115, 1130– 1190, DOI: 10.1021/cr500336u
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247b
Preparation and utility of organic pentafluorosulfanyl-containing compounds
Savoie, Paul R.; Welch, John T.
Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 1130-1190CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review on prepn. of pentafluorosulfanyl-contg. compds. and their use in a variety of synthetic org. reactions.
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(c) von Hahmann, C. N.; Savoie, P. R.; Welch, J. T. Reactions of organic pentafluorosulfanyl-containing compounds. Curr. Org. Chem. 2015, 19, 1592– 1618, DOI: 10.2174/1385272819666150601211131
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247c
Reactions of Organic Pentafluorosulfanyl-containing Compounds
von Hahmann, Cortney N.; Savoie, Paul R.; Welch, John T.
Current Organic Chemistry (2015), 19 (16), 1592-1618CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
A review. While significant attention was focused on the incorporation of fluorine in C-F bonds, or the introduction of a trifluoromethyl (CF3) groups, previously, the role of SF5 group was highlighted in this review. The SF5 group has a similar electron withdrawing effect as the CF3 group yet the SF5 group is significantly more lipophilic. Combining these properties resulted in the proclivity of SF5-contg. arenes to undergo displacement reactions. The hydrophobicity of the SF5-group was used to direct the conformation of SF5-contg. peptides. The profound dipole assocd. with pentafluorosulfanylation was successfully used to direct the stereochem. of the Staudinger reaction. The greater steric demand of the SF5 group relative to the CF3 group had dramatically effected the conformation of small mols. by encumbering rotational freedom. The influence of the SF5-group on the reactions of alkanes, alkenes, alkynes, arenes and various functional groups was reviewed.
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248
Stump, B.; Eberle, C.; Schweizer, W. B.; Kaiser, M.; Brun, R.; Krauth-Siegel, R. L.; Lentz, D.; Diederich, F. Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines. ChemBioChem 2009, 10, 79– 83, DOI: 10.1002/cbic.200800565
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249
Altomonte, S.; Baillie, G. L.; Ross, R. A.; Riley, J.; Zanda, M. The pentafluorosulfanyl group in cannabinoid receptor ligands: synthesis and comparison with trifluoromethyl and tert-butyl analogues. RSC Adv. 2014, 4, 20164– 20176, DOI: 10.1039/C4RA01212G
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249
The pentafluorosulfanyl group in cannabinoid receptor ligands: synthesis and comparison with trifluoromethyl and tert-butyl analogues
Altomonte, Stefano; Baillie, Gemma L.; Ross, Ruth A.; Riley, Jennifer; Zanda, Matteo
RSC Advances (2014), 4 (39), 20164-20176CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
An array of cannabinoid ligands, substituted pyrazolecarboxamides I (R1 = 5-Br-2-thienyl, 4-ClC6H4; R2 = 2,4-Cl2C6H3, 2,4-F2C6H3; R3 = 3-F3CC6H4, 3-F5SC6H4, 3-t-BuC6H4, 4-F3CC6H4, 4-F5SC6H4, 4-t-BuC6H4) were efficiently synthesized. In general, the SF5-substituted ligands showed higher lipophilicity (i.e. log P values) than the CF3 counterparts and lower lipophilicity than the tert-Bu analogs. In terms of pharmacol. activity, SF5 pyrazoles generally showed slightly higher or equiv. CB1 receptor affinity (Ki), always in the nanomolar range, and selectivity towards the CB2 relative to both CF3 and tert-Bu analogs. Functional β-arrestin recruitment assays were used to det. equil. dissocn. consts. (Kb) and showed that all of the tested SF5 and CF3 compds. were CB1 neutral antagonists. These results confirm the possibility of successfully using an arom. SF5 group as a stable, synthetically accessible and effective bioisosteric analog of the electron-withdrawing CF3 group and possibly also of bulky aliph. groups for drug discovery and development applications.
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Sun, L.; Bera, H.; Chui, W. K. Synthesis of pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors of thymidine phosphorylase. Eur. J. Med. Chem. 2013, 65, 1– 11, DOI: 10.1016/j.ejmech.2013.03.063
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(b) Sun, L.; Li, J.; Bera, H.; Dolzhenko, A. V.; Chiu, G. N. C.; Chui, W. K. Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1, 5-a][1,3,5]triazines as thymidine phosphorylase inhibitors. Eur. J. Med. Chem. 2013, 70, 400– 410, DOI: 10.1016/j.ejmech.2013.10.022
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The synthesis and biological activity of pentafluorosulfanyl analogs of fluoxetine, fenfluramine, and norfenfluramine
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Bioorganic & Medicinal Chemistry (2007), 15 (21), 6659-6666CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
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Abstract
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Figure 1
Figure 1. Key drug–target interactions between 29 and the PI3Kα enzyme and conformational bias provided by an intramolecular O to S interaction.
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Figure 2
Figure 2. Atropoisomerism associated with 4-(perfluoropropan-2-yl)-1H-indazol-5-amine.
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Scheme 1
Scheme 1. Metabolism of 63 and the Release of 66
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Scheme 2
Scheme 2. Metabolic Activation Pathway Deduced for the DPP-4 Inhibitor 67
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Scheme 3
Scheme 3. Cytochrome P450-Mediated Metabolism of the 1,3-Benzodioxole Moiety to a MI Complex
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Figure 3
Figure 3. Preferred conformation of 82 at the GABA_A receptor (A) and the GABA_C receptor and the transaminase enzyme (B) deduced from an evaluation of 83 and 84.
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Figure 4
Figure 4. Proposed active conformation of NMDA at the GluN2A and GluN2B receptors after analysis of 91 and 92.
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Figure 5
Figure 5. Conformational preferences of N-acetyl-proline methyl ester (94) (A), N-acetyl-4-(R)-fluoro-l-proline methyl ester (95) (B), and N-acetyl-4-(S)-fluoro-l-proline methyl ester (96) (C).
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Figure 6
Figure 6. Acetamide conformation of 94 depicting an n → π* interaction.
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Figure 7
Figure 7. Geometry of 1,1-difluoroalkanes (A), the 1,4-di-CF₂ motif (B), and conformational preferences for 1,2-difluoro- (C) and 1,3-difluoro-alkanes (D).
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Scheme 4
Scheme 4. Metabolism of 132
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Figure 8
Figure 8. Core structures of MMPs of N-phenylamides and benzamides examined in a PAMPA.
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Figure 9
Figure 9. Comparison of the dipole moments and vectors of difluorinated benzenes and azines.
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Figure 10
Figure 10. Key interactions between CHK1 kinase and 190 in the cocrystal structure.
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Figure 11
Figure 11. Structures and cathepsin L inhibitory data for 195–204.
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Figure 12
Figure 12. Proposed relationship between a piperazine lone pair of electrons and the fluorine atom of a 4-fluoropiperidine ring.
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Figure 13
Figure 13. Key interactions between inhibitor 218 and thrombin.
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Figure 14
Figure 14. Key drug–target interactions between the CF₃ substituent of 224 and the p53 protein.
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Figure 15
Figure 15. Key drug–target interactions between inhibitor 227 and BTK.
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Figure 16
Figure 16. Calculated energies of the σ-hole and π-hole associated with perfluorotoluene.
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Figure 17
Figure 17. Key interactions between 234 and IDH2 in the cocrystal stucture.(110b)
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Figure 18
Figure 18. Key interactions between 235 and the NmrA-like family domain containing protein 1 NMRAL1 in the cocrystal complex.(111)
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Figure 19
Figure 19. Proposed dipole interactions between 248 and Aurora A kinase leading to a conformational change in the DFG loop of the enzyme.
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Figure 20
Figure 20. Dipole moments and vectors that illustrate isosterism between an amide moiety and fluorinated alkene derivatives that contrasts with simpler alkenes.
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Figure 21
Figure 21. Key interactions between and FVIIa and the benzamidine-based inhibitor 304.
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Figure 22
Figure 22. Key drug–target interactions between 309 and the HCV NS5B polymerase protein.
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Figure 23
Figure 23. Key drug–target interactions between MEK1 and inhibitor 314.
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Figure 24
Figure 24. Structural overlays of 82 with 318 and 319 illustrating C–F and C═O mimicry.
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Scheme 5
Scheme 5. Metabolism of 331–333 by Steroid 5α-Reductase
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Scheme 6
Scheme 6. Reaction Process Catalyzed by α,β-Dihydroxyacid Dehydratase
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Figure 25
Figure 25. Isosteric relationship between formaldehyde and 1,1-difluoroethylene.
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Scheme 7
Scheme 7. TDP-l-rhamnose Synthase-Catalyzed Reduction of 342 to 343
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Scheme 8
Scheme 8. Postulated Reaction Pathway of 341 with TDP-l-rhamnose Synthase
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Figure 26
Figure 26. Incorporation of the CF₃CH₂NH motif in a polypeptide backbone in register (B) or in a partially retro-inverted configuration (C) that mimics the amide of a conventional polypeptide (A).
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Figure 27
Figure 27. Functional aspects of the mimicry between an amide and a sulfonamide moiety and CF₃CH₂NH and CHF₂CH₂NH.
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Figure 28
Figure 28. Bond angles and lengths that illustrate topological mimesis between a urea and a fluoroenamide.
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Figure 29
Figure 29. Calculated conformational preferences for α-fluoromethyl and α,α-difluoromethyl secondary amides.
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Figure 30
Figure 30. Conformational preferences of the α-fluorinated enantiomers of 413 designed to illuminate the bound conformation.
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Figure 31
Figure 31. Topologies and bond lengths associated with α-fluoro-substituted amides 416–418 and urea 419 in the solid state.
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Figure 32
Figure 32. Preferred conformation of a 2′-α-fluoro-substituted ribose compared with a 2′-β-fluoro substituted isomer and a 2′-β, 2′-α-difluoro-substituted ribose ring.
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Figure 33
Figure 33. Key H-bonding interactions between a 2′-methyl ribose moiety (436) and the 2′-fluoro-2′-methyl homologue that is the ribose hallmark of 434.
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Figure 34
Figure 34. Intermolecular H-bond observed in the single-crystal X-ray structure of oxadiazole 449.
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Figure 35
Figure 35. Illustration of the functional mimicry between RSH and RCF₂H in P₁ residues incorporated into 450 and 452.
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Figure 36
Figure 36. Geometric parameters for the phosphate, phosphonate, and difluoromethylenephosphonate moieties.
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Figure 37
Figure 37. Proposed isosterism between anisole and (1,1-difluoroethyl)benzene.
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Figure 38
Figure 38. Conformational aspects of anisole, PhOCF₃, and PhOCHF₂.
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Figure 39
Figure 39. Comparison of the shapes of the CF₃ and SF₅ substituents.
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Figure 40
Figure 40. Proposed drug–target interactions between 554 and T. cruzi trypanothione reductase based on docking of the ligand into the active site of the enzyme.
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  Langmuir, Irving
  Journal of the American Chemical Society (1919), 41 (), 1543-59CODEN: JACSAT; ISSN:0002-7863.
  cf. C. A. 3, 1554. In compds. other than those of C the number of electron pairs held in common is not always the same as the number of valence bonds that have usually been assumed; thence it is proposed that the number of pairs of electrons which any atom shares with adjacent atoms be called the covalence of the atom. Pairs of compds. such as CO2 and N2O or CO and N2 which show extraordinary agreement in physical properties and which (according to the octet theory) have the same number and arrangement of electrons in the mol. are called isosteric: compds. or isosteres. The term is applicable not only to mols. but to radicals or groups of atoms which hold pairs of electrons in common. Thus a mol. and an ion may be isosteres, e. g., Ne, Na+ Mg++, Al+++, O- and F- are all isosteric with one another. A table of 21 types of isosterism is given. When isosteric mols. are also isoelectric, that is when they have the same total charge on the comolecule, all of their phys. properties should be closely similar. (Comolecules are groups of atoms held together by pairs of electrons shared by adjacent atoms.) This is shown to be true for cyanate and azide ions and the compds. derived from them. No direct comparison can be made of the phys. properties of isosteres having different electric charges. Thus Na salts do not resemble Ne, although Na+ is isosteric with Ne. But another type of comparison can be made as to the actual isosterism of comolecules with different charges. For example, A and N2 resemble each other closely; therefore chloride ion, isosteric with A, should have a close resemblance to the cyanide ion which is isosteric with N2. The similarity of chlorides and cynides is thus directly correlated with that between A and N. A similar close relationship between K salts and NH4 salts can be derived, since A is an isostere of K+ and CH4 is an isostere of NH4+, while the 2 gases are alike in all their physical properties. Since the Na+ and F- ions are isosteric, while Mg++ and O-- are also isosteric, MgO and NaF should be identical in crystal structure. Both are cubic, and they have the same crystal structure according to the X-ray spectra, except that the atoms are drawn closer together by the greater forces in MgO. Thus they should be looked upon as isomorphous. Other similar pairs are MgF2 and Na2O, KCl and CaS, K2S and CaCl2, Cu2S and ZnCl2, KNO3 and SrCO3, KClO4, and SrSO4, etc. Crystalline form depends on structure as given by the octet theory, which gives a true picture of the constitutions of cryst. solids. The following conclusions are justified: The covalence of Na, K, Cl (in chlorides) is zero; the covalence of the central atom is 4 in nitrates, carbonates, sulfates, perchlorates, phosphates, permanganates, chromates, selenates, arsenates, borofluorides, etc.; carbonates and sulfides are not isomorphous, the covalence of the central atom being 4 and 3, resp.; nitrates and chlorates are not isomorphous, the covalency of the chlorine being 3 in chlorates. The applicability of the octet theory to complex inorg. compds. receives further confirmation by its ability to explain such cases of isomorphism. as between Na2BeF4 and MnCl2.4H2O, K2SO4 and ZnI2.4NH3, K2SnCl4.2H2O and K2FeCl5.H2O, NaAlSi3O8 and CaAl2Si2O8.
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3. 3
  Fried, J.; Sabo, E. F. 9α-Fluoro derivatives of cortisone and hydrocortisone. J. Am. Chem. Soc. 1954, 76, 1455– 1456, DOI: 10.1021/ja01634a101
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  3
  9α-Fluoro derivatives of cortisone and hydrocortisone
  Fried, Josef; Sabo, Emily F.
  Journal of the American Chemical Society (1954), 76 (), 1455-6CODEN: JACSAT; ISSN:0002-7863.
  cf. C.A. 49, 6298e. 4-Pregnen-9β, 11β-oxido-21-ol-3,20-dione (I) with anhyd. HF in CHCl3 4.5 h. at 0° yielded 50% 9α-fluorohydrocortisone acetate (II), m. 233-4°, [α]D23 123° (c 0.64, CHCl3); II showed 10.7 times the activity of cortisone acetate (III) in the rat-liver glycogen assay. II with MeONa yielded 9α-fluorohydrocortisone (IV), m. 260-2° (decompn.), [α]D23 139° (c 0.55, EtOH). II with chromic acid yielded 9α-fluorocortisone acetate (V), m. 254-5°, [α]D23 155° (c 0.45, CHCl3). Deacetylation of V yielded the alc., m. 261-2°, [α]D23 144° (c 0.41, CHCl3), with 9.0 ± 2.7 times the activity of III. In addn. to II, the reaction of I with HF yielded 10% of an isomer (V), m. 259-62°, [α]D23 272° (c 0.53, EtOH), in which the epoxide group had rearranged to form a double bond and a readily acylatable OH group. V consumed 1 mol of perphthalic acid to give an epoxide, m. 213-14° (decompn.), [α]D23 237° (c 0.59, CHCl3). V with (EtCO)2O and pyridine at room temp. yielded a propionate, m. 261-4°, [α]D22 260° (c 0.40, CHCl3). V with MeSO2Cl in pyridine at 0° yielded a mesylate, m. 151-2° (decompn.), [α]D23 260° (c 0.54, CHCl3).
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4. 4
  (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 8315– 8359, DOI: 10.1021/acs.jmedchem.5b00258
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  4a
  Applications of Fluorine in Medicinal Chemistry
  Gillis, Eric P.; Eastman, Kyle J.; Hill, Matthew D.; Donnelly, David J.; Meanwell, Nicholas A.
  Journal of Medicinal Chemistry (2015), 58 (21), 8315-8359CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review with meta-anal. The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties assocd. with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a mol. can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addn., 18F has been established as a useful positron emitting isotope for use with in vivo imaging technol. that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug mols. and applications in positron emission tomog.
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  (b) Zhu, W.; Wang, J.; Wang, S.; Gu, Z.; Aceña, J. L.; Izawa, K.; Liu, H.; Soloshonok, V. A. Recent advances in the trifluoromethylation methodology and new CF₃-containing drugs. J. Fluorine Chem. 2014, 167, 37– 54, DOI: 10.1016/j.jfluchem.2014.06.026
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  4b
  Recent advances in the trifluoromethylation methodology and new CF3-containing drugs
  Zhu, Wei; Wang, Jiang; Wang, Shuni; Gu, Zhanni; Acena, Jose Luis; Izawa, Kunisuke; Liu, Hong; Soloshonok, Vadim A.
  Journal of Fluorine Chemistry (2014), 167 (), 37-54CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
  A review. This review provides a brief assessment of the methodol. field of trifluoromethylation and its possible impact on the development of new CF3-contg. pharmaceuticals. Structural aspects of five new drug-candidates, [tafenoquine (arom. CF3), roniciclib (heteroarom. CF3), BAY-38-7271 (aliph. CF3), sonidegib (O-CF3) and navitoclax (S-CF3)] currently under the development in phase II and III clin. studies, and their biol. properties, therapeutic area and synthesis are critically discussed.
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  (c) Hodgetts, K. J.; Combs, K. J.; Elder, A. M.; Harriman, G. C. The role of fluorine in the discovery and optimization of CNS agents: modulation of drug-like properties. Annu. Rep. Med. Chem. 2010, 45, 429– 448, DOI: 10.1016/S0065-7743(10)45026-5
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  (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320– 330, DOI: 10.1039/B610213C
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  Fluorine in medicinal chemistry
  Purser, Sophie; Moore, Peter R.; Swallow, Steve; Gouverneur, Veronique
  Chemical Society Reviews (2008), 37 (2), 320-330CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. It has become evident that fluorinated compds. have a remarkable record in medicinal chem. and will play a continuing role in providing lead compds. for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.
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  4e
  The Many Roles for Fluorine in Medicinal Chemistry
  Hagmann, William K.
  Journal of Medicinal Chemistry (2008), 51 (15), 4359-4369CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review.
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  (f) Böhm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. Fluorine in medicinal chemistry. ChemBioChem 2004, 5, 637– 643, DOI: 10.1002/cbic.200301023
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  Fluorine in medicinal chemistry
  Bohm Hans-Joachim; Banner David; Bendels Stefanie; Kansy Manfred; Kuhn Bernd; Muller Klaus; Obst-Sander Ulrike; Stahl Martin
  Chembiochem : a European journal of chemical biology (2004), 5 (5), 637-43 ISSN:1439-4227.
  Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.
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  (g) Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007, 317, 1881– 1886, DOI: 10.1126/science.1131943
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  4g
  Fluorine in Pharmaceuticals: Looking Beyond Intuition
  Mueller, Klaus; Faeh, Christoph; Diederich, Francois
  Science (Washington, DC, United States) (2007), 317 (5846), 1881-1886CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  A review. Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all phys. and adsorption, distribution, metab., and excretion properties of a lead compd. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on mol. conformation of the drug, has only recently begun. Here, we review exptl. progress in this vein and add complementary anal. based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.
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  (h) Shah, P.; Westwell, A. D. The role of fluorine in medicinal chemistry. J. Enzyme Inhib. Med. Chem. 2007, 22, 527– 540, DOI: 10.1080/14756360701425014
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  4h
  The role of fluorine in medicinal chemistry
  Shah, Poonam; Westwell, Andrew D.
  Journal of Enzyme Inhibition and Medicinal Chemistry (2007), 22 (5), 527-540CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)
  A review. The small and highly electroneg. fluorine atom can play a remarkable role in medicinal chem. Selective installation of fluorine into a therapeutic or diagnostic small mol. candidate can enhance a no. of pharmacokinetic and physicochem. properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a no. of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomog. (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chem. applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimize mol. properties.
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  (i) Maienfisch, P.; Hall, R. G. The importance of fluorine in the life science industry. Chimia 2004, 58, 93– 99, DOI: 10.2533/000942904777678091
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  4i
  The importance of fluorine in the life science industry
  Maienfisch, Peter; Hall, Roger G.
  Chimia (2004), 58 (3), 93-99CODEN: CHIMAD; ISSN:0009-4293. (Swiss Chemical Society)
  Fluorine-contg. compds. are at the leading edge of many new developments in the life science industry. In recent years a steady increase in the no. of fluorinated org. mols. reaching com. status as crop protection products and pharmaceutical drugs has been obsd.: in 1978, ∼600 pesticides were known, but only approx. 25 (4%) contained fluorine. Today, fluorine-contg. compds. account for more than 17% of all com. available crop protection agents and many others are currently under development. The structures of the fluorine-contg. development compds. proposed for ISO common names between 1997 and 2002 are highlighted in this paper. In the pharmaceutical area around 220 fluorinated drugs were on the market in 1990, representing ∼8% of all synthetic drugs. Six years later already more than 1500 fluorine-contg. drugs were under development. Fluorine-contg. compds. have also been successful in the market-place, such as the insecticides fipronil and lambda-cyhalothrin, the fungicides epoxiconazole and trifloxystrobin, the herbicides trifluralin and clodinafop, and the pharmaceutical blockbusters Fluoxetine (Prozac), Paroxetine (Paxil), Ciprofloxacin (Cipro) and Cisaprid (Propulsid). This success is mainly due to the fact that selectively fluorinated compds. can exhibit dramatically improved potency when compared to the non-fluorinated analogs. The incorporation of fluorine into a biol. active compd. alters the electronic, lipophilic and steric parameters and can critically increase the intrinsic activity, the chem. and metabolic stability, and the bioavailability. The pos. effects of fluorine on the biol. efficiency is outlined by three examples: in the chem. class of herbicidal thiatriazines, the presence or the absence of fluorine leads to dramatic effects on the biol. activity; the metabolic stability and the pharmacokinetics of aminopyrazinone acetamide thrombin inhibitors were improved by the introduction of fluorine, and in a novel class of insecticides/acaricides any modification of the gem-difluorovinyl group results in a strong decrease of biol. activity.
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5. 5
  (a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 2016, 116, 422– 518, DOI: 10.1021/acs.chemrev.5b00392
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  5a
  Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II-III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas
  Zhou, Yu; Wang, Jiang; Gu, Zhanni; Wang, Shuni; Zhu, Wei; Acena, Jose Luis; Soloshonok, Vadim A.; Izawa, Kunisuke; Liu, Hong
  Chemical Reviews (Washington, DC, United States) (2016), 116 (2), 422-518CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. We focus herein on a new collection of 51 fluorine-contg. mols. that either were approved after 2011 by the corresponding agencies or still are on clin. development. These compds. cover a large no. of therapeutic areas and, on this occasion, we decided to classify them according to the no. of fluorine atoms or fluorinated moieties. In each case, the structures and modes of action of these new drugs are revised, with a particular focus on the role of fluorine in the biol. and pharmaceutical properties, when appropriate. Finally, representative synthetic routes are highlighted.
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  (b) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem. Rev. 2014, 114, 2432– 2506, DOI: 10.1021/cr4002879
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  5b
  Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001-2011)
  Wang, Jiang; Sanchez-Rosello, Maria; Acena, Jose Luis; del Pozo, Carlos; Sorochinsky, Alexander E.; Fustero, Santos; Soloshonok, Vadim A.; Liu, Hong
  Chemical Reviews (Washington, DC, United States) (2014), 114 (4), 2432-2506CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A historic review. As expected from the fluorine position on the periodic table of elements, it possesses some extreme properties, in particular, ultimate electronegativity and oxidn. potential. Therefore,elemental fluorine can not be prepd. by chem. reaction, and its isolation in 1886 by Henri Moissan required scientific ingenuity and great personal courage. His historic effort earned him a Noble Prize (1906), and the developed electrolysis method is still in use for industrial prodn. of fluorine gas. However, further development of fluorine chem. was extremely sluggish, pursued by a handful of experts capable of handling the violent gas using specially designed lab. equipment. Industrial-scale prodn. of fluorochems. dates back to late 1930s. Currently, there are about 200 pharmaceuticals containingfluorine, including the 40 new compds. discussed in this review. One may agree that the contribution of the past decade indicates a significant 20% increase in the no. of fluorinated drugs on the market.
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  (c) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. Data-mining for sulfur and fluorine: an evaluation of pharmaceuticals to reveal opportunities for drug design and discovery. J. Med. Chem. 2014, 57, 2832– 2842, DOI: 10.1021/jm401375q
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  5c
  Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery
  Ilardi, Elizabeth A.; Vitaku, Edon; Njardarson, Jon T.
  Journal of Medicinal Chemistry (2014), 57 (7), 2832-2842CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. Among carbon, hydrogen, oxygen, and nitrogen, sulfur and fluorine are both leading constituents of the pharmaceuticals that comprise our medicinal history. In efforts to stimulate the minds of both the general public and expert scientist, statistics were collected from the trends assocd. with therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new graphical montage compilation: disease focused pharmaceuticals posters. Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronol. and classified according to an assocn. with a particular clin. indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qual. conclusions in this article aim to promote innovative insights into drug development.
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6. 6
  (a) Jeschke, P. The unique role of fluorine in the design of active ingredients for modern crop protection. ChemBioChem 2004, 5, 570– 589, DOI: 10.1002/cbic.200300833
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  6a
  The unique role of fluorine in the design of active ingredients for modern crop protection
  Jeschke, Peter
  ChemBioChem (2004), 5 (5), 570-589CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The task of inventing and developing active ingredients with useful biol. activities requires a search for novel chem. substructures. This process may trigger the discovery of whole classes of chems. of potential com. interest. Similar biol. effects can often be achieved by completely different compds. However, compds. within a given structural family may exhibit quite different biol. activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compd., its interaction with the active site of the target protein, as well as its physicochem., pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated org. compds. represent an important and growing family of com. agrochems. A no. of recently developed agrochem. candidates represent novel classes of chem. compds. with new modes of action; several of these compds. contain new fluorinated substituents. However, the complex structure-activity relationships assocd. with biol.-active mols. mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a mol. at which fluorine substitution will result in optimal desired effects.
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  (b) Jeschke, P. The unique role of halogen substituents in the design of modern agrochemicals. Pest Manage. Sci. 2010, 66, 10– 27, DOI: 10.1002/ps.1829
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  6b
  The unique role of halogen substituents in the design of modern agrochemicals
  Jeschke, Peter
  Pest Management Science (2010), 66 (1), 10-27CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)
  A review. The past 30 years have witnessed a period of significant expansion in the use of halogenated compds. in the field of agrochem. research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochem. with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, esp. in synthetic methods for particular halogen-substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the no. of com. products contg. mixed' halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addn. to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine-substituted agrochems. throughout the twenty-first century. A no. of these recently developed agrochem. candidates contg. halogen substituents represent novel classes of chem. compds. with new modes of action. However, the complex structure-activity relationships assocd. with biol. active mols. mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a mol. at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilization of halogens and their unique role in the design of modern agrochems., exemplified by various com. products from Bayer CropScience coming from different agrochem. areas. Copyright © 2009 Society of Chem. Industry.
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  (c) Fujiwara, T.; O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluorine Chem. 2014, 167, 16– 29, DOI: 10.1016/j.jfluchem.2014.06.014
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  Successful fluorine-containing herbicide agrochemicals
  Fujiwara, Tomoya; O'Hagan, David
  Journal of Fluorine Chemistry (2014), 167 (), 16-29CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
  A review. Of the herbicides licensed worldwide, currently around 25% contain at least one fluorine atom and many contain multiple fluorines in the form of difluoro- and trifluoromethyl groups. Fluorine-contg. compds. have made a significant contribution to the development of products for the agrochems. industry and many organofluorine entities have found stable market positions. In this review we highlight the most important fluorinated herbicides in terms of their global use. The compds. are grouped by mode of action. A synthesis route is described for each compd. although the synthesis presented may not actually be the industrial process.
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  (d) Jeschke, P. Latest generation of halogen-containing pesticides. Pest Manage. Sci. 2017, 73, 1053– 1056, DOI: 10.1002/ps.4540
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  Latest generation of halogen-containing pesticides
  Jeschke, Peter
  Pest Management Science (2017), 73 (6), 1053-1066CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)
  Agriculture is confronted with enormous challenges, from prodn. of enough high-quality food to water use, environmental impacts and issues combined with a continually growing world population. Modern agricultural chem. has to support farmers by providing innovative agrichems., used in applied agriculture. In this context, the introduction of halogen atoms into an active ingredient is still an important tool to modulate the properties of new crop protection compds. Since 2010, around 96% of the launched products (herbicides, fungicides, insecticides/acaricides and nematicides) contain halogen atoms. The launched nematicides contain the largest no. of halogen atoms, followed by insecticides/acaricides, herbicides and fungicides. In this context, fungicides and herbicides contain in most cases fluorine atoms, whereas nematicides and insecticides contain in most cases 'mixed' halogen atoms, for example chlorine and fluorine. This review gives an overview of the latest generation of halogen-contg. pesticides launched over the past 6 years and describes current halogen-contg. development candidates. © 2017 Society of Chem. Industry.
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7. 7
  (a) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem., Int. Ed. 2013, 52, 8214– 8264, DOI: 10.1002/anie.201206566
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  Introduction of Fluorine and Fluorine-Containing Functional Groups
  Liang, Theresa; Neumann, Constanze N.; Ritter, Tobias
  Angewandte Chemie, International Edition (2013), 52 (32), 8214-8264CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.
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  (b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and tri-fluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 2015, 115, 826– 870, DOI: 10.1021/cr500277b
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  (c) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Functionalization of fluorinated molecules by transition metal-mediated C–F bond activation to access fluorinated building blocks. Chem. Rev. 2015, 115, 931– 972, DOI: 10.1021/cr500257c
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  (d) Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V. Polyfluorinated ethanes as versatile fluorinated C2-building blocks for organic synthesis. Chem. Rev. 2015, 115, 973– 1050, DOI: 10.1021/cr500465n
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  7d
  Polyfluorinated Ethanes as Versatile Fluorinated C2-Building Blocks for Organic Synthesis
  Nenajdenko, Valentine G.; Muzalevskiy, Vasiliy M.; Shastin, Aleksey V.
  Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 973-1050CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. Prepn. and reactions of polyfluorinated ethanes are addressed. Fluorinated derivs. of alkanes, alkenes, ethers, sulfides, carboxylic acids, sulfinic and sulfonic acids, alcs. and ketones, and arom. and heteroarom. compds. were efficiently prepd. using cheap and available starting materials.
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  (e) Yerien, D. E.; Barata-Vallejo, S.; Postigo, A. Difluoromethylation reactions of organic compounds. Chem. - Eur. J. 2017, 23, 14676– 14701, DOI: 10.1002/chem.201702311
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  Difluoromethylation Reactions of Organic Compounds
  Yerien, Damian E.; Barata-Vallejo, Sebastian; Postigo, Al
  Chemistry - A European Journal (2017), 23 (59), 14676-14701CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The difluoromethylation strategies to functionalize different families of org. compds., for the late-stage introduction of a CF2H or CF2Y moieties into org. substrates was presented. These methodologies include, (i) a metal-photoredox catalysis; (ii) transition metal-catalyzed thermal protocols; and (iii) transition-metal-free strategies.
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8. 8
  (a) O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C-F bond. Chem. Soc. Rev. 2008, 37, 308– 319, DOI: 10.1039/B711844A
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  8a
  Understanding organofluorine chemistry. An introduction to the C-F bond
  O'Hagan, David
  Chemical Society Reviews (2008), 37 (2), 308-319CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. Fluorine is the most electroneg. element in the periodic table. When bound to carbon it forms the strongest bonds in org. chem. and this makes fluorine substitution attractive for the development of pharmaceuticals and a wide range of specialty materials. Although highly polarized, the C-F bond gains stability from the resultant electrostatic attraction between the polarized Cδ+ and Fδ- atoms. This polarity suppresses lone pair donation from fluorine and in general fluorine is a weak coordinator. However, the C-F bond has interesting properties which can be understood either in terms of electrostatic/dipole interactions or by considering stereoelectronic interactions with neighboring bonds or lone pairs. In this tutorial review these fundamental aspects of the C-F bond are explored to rationalize the geometry, conformation and reactivity of individual organofluorine compds.
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  (b) Mikami, K.; Itoh, Y.; Yamanaka, M. Fluorinated carbonyl and olefinic compounds: basic character and asymmetric catalytic reactions. Chem. Rev. 2004, 104, 1– 16, DOI: 10.1021/cr030685w
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  8b
  Fluorinated Carbonyl and Olefinic Compounds: Basic Character and Asymmetric Catalytic Reactions
  Mikami, Koichi; Itoh, Yoshimitsu; Yamanaka, Masahiro
  Chemical Reviews (Washington, DC, United States) (2004), 104 (1), 1-16CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review.
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9. 9
  Clark, T.; Murray, J. S.; Lane, P.; Politzer, P. Why are dimethyl sulfoxide and dimethyl sulfone such good solvents?. J. Mol. Model. 2008, 14, 689– 697, DOI: 10.1007/s00894-008-0279-y
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  9
  Why are dimethyl sulfoxide and dimethyl sulfone such good solvents?
  Clark, Timothy; Murray, Jane S.; Lane, Pat; Politzer, Peter
  Journal of Molecular Modeling (2008), 14 (8), 689-697CODEN: JMMOFK; ISSN:0948-5023. (Springer GmbH)
  The authors carried out B3PW91 and MP2-FC computational studies of DMSO, (CH3)2SO, and di-Me sulfone, (CH3)2SO2. The objective was to establish quant. the basis for their high polarities and b.ps., and their strong solvent powers for a variety of solutes. Natural bond order analyses show that the sulfur-oxygen linkages are not double bonds, as widely believed, but rather are coordinate covalent single S+→O- bonds. The calcd. electrostatic potentials on the mol. surfaces reveal several strongly pos. and neg. sites (the former including σ-holes on the sulfurs) through which a variety of simultaneous intermol. electrostatic interactions can occur. A series of examples is given. In terms of these features the striking properties of DMSO and di-Me sulfone, their large dipole moments and dielec. consts., their high b.ps. and why they are such good solvents, can readily be understood.
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10. 10
  (a) Park, K. B.; Kitteringham, N. R. Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metab. Rev. 1994, 26, 605– 643, DOI: 10.3109/03602539408998319
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  10a
  Effects of fluorine substitution on drug metabolism: Pharmacological and toxicological implications
  Park, B. Kevin; Kitteringham, Neil R.
  Drug Metabolism Reviews (1994), 26 (3), 605-43CODEN: DMTRAR; ISSN:0360-2532.
  A review with 112 refs. Physicochem. properties of fluorinated drugs, fluorine substitution effect on drug metab., and fluorinated compds. as enzyme inhibitors are discussed.
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  (b) Murphy, C. D.; Sandford, G. Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity. Expert Opin. Drug Metab. Toxicol. 2015, 11, 589– 599, DOI: 10.1517/17425255.2015.1020295
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  10b
  Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity
  Murphy, Cormac D.; Sandford, Graham
  Expert Opinion on Drug Metabolism & Toxicology (2015), 11 (4), 589-599CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)
  A review. Introduction: Fluorine's unique physicochem. properties make it a key element for incorporation into pharmacol. active compds. Its presence in a drug can alter a no. of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. Areas covered: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailability and how the effects obsd. are related to the physicochem. characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biol. systems for fluorinated drug prodn. is discussed. Expert opinion: The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technol. for the manufg. scale and new reagents and methods are required to meet the demands for the prepn. of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to det. the nature of transformation products that may cause ecol. damage.
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11. 11
  (a) Meanwell, N. A. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem. Res. Toxicol. 2011, 24, 1420– 1456, DOI: 10.1021/tx200211v
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  11a
  Improving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and Safety
  Meanwell, Nicholas A.
  Chemical Research in Toxicology (2011), 24 (9), 1420-1456CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
  A review. The development of small mol. drug candidates from the discovery phase to a marketed product continues to be a challenging enterprise with very low success rates that have fostered the perception of poor productivity by the pharmaceutical industry. Although there have been significant advances in preclin. profiling that have improved compd. triaging and altered the underlying reasons for compd. attrition, the failure rates have not appreciably changed. As part of an effort to more deeply understand the reasons for candidate failure, there has been considerable interest in analyzing the physicochem. properties of marketed drugs for the purpose of comparing with drugs in discovery and development as a means capturing recent trends in drug design. The scenario that has emerged is one in which contemporary drug discovery is thought to be focused too heavily on advancing candidates with profiles that are most easily satisfied by mols. with increased mol. wt. and higher overall lipophilicity. The preponderance of mols. expressing these properties is frequently a function of increased arom. ring count when compared with that of the drugs launched in the latter half of the 20th century and may reflect a preoccupation with maximizing target affinity rather than taking a more holistic approach to drug design. These attributes not only present challenges for formulation and absorption but also may influence the manifestation of toxicity during development. By providing some definition around the optimal physicochem. properties assocd. with marketed drugs, guidelines for drug design have been developed that are based largely on calcd. parameters and which may readily be applied by medicinal chemists as an aid to understanding candidate quality. The physicochem. properties of a mol. that are consistent with the potential for good oral absorption were initially defined by Lipinski, with addnl. insights allowing further refinement, while deeper analyses have explored the correlation with metabolic stability and toxicity. These insights have been augmented by careful analyses of physicochem. aspects of drug-target interactions, with thermodn. profiling indicating that the signature of best-in-class drugs is a dependence on enthalpy to drive binding energetics rather than entropy, which is dependent on lipophilicity. Optimization of the entropic contribution to the binding energy of a ligand to its target is generally much easier than refining the enthalpic element. Consequently, in the absence of a fundamental understanding of the thermodn. complexion of an interaction, the design of mols. with increased lipophilicity becomes almost inevitable. The application of ligand efficiency, a measure of affinity per heavy atom, group efficiency, which assesses affinity in the context of structural changes, and lipophilic ligand efficiency, which relates potency to lipophilicity, offer less sophisticated but practically useful anal. algorithms to assess the quality of drug-target interactions. These parameters are readily calcd. and can be applied to lead optimization programs in a fashion that helps to maximize potency while minimizing the kind of lipophilic burden that has been dubbed "mol. obesity". Several recently described lead optimization campaigns provide illustrative, informative, and productive examples of the effect of paying close attention to carefully controlling physicochem. properties by monitoring ligand efficiency and lipophilic ligand efficiency. However, to be successful during the lead optimization phase, drug candidate identification programs will need to adopt a holistic approach that integrates multiple parameters, many of which will have unique dependencies on both the drug target and the specific chemotype under prosecution. Nevertheless, there are many important drug targets that necessitate working in space beyond that which has been defined by the retrospective analyses of marketed drugs and which will require adaptation of some of the guideposts that are useful in directing lead optimization.
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  .
  (b) Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 2016, 29, 564– 616, DOI: 10.1021/acs.chemrestox.6b00043
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  11b
  Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space
  Meanwell, Nicholas A.
  Chemical Research in Toxicology (2016), 29 (4), 564-616CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
  Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The phys., biol., and toxicol. properties of a drug candidate are inextricably linked to its structure, and once a mol. has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biol. properties of a mol. from an anal. of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a mol. is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clin. trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective anal. of drug design practices over the past decade has focused attention on the perception that contemporary mols. are unnecessarily obese, burdened by high mol. wt. and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chem. community with practical guideposts to enhancing compd. quality in the drug design phase and which can readily be applied, a series of efficiency indexes have been proposed that attempt to define aspects of compd. quality in the context of a series of physicochem. parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a mol. on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compd. aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, mols. that fall into space beyond that assocd. with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clin. therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compd. quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success.
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12. 12
  Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455
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  12
  Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery
  Huchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, Klaus
  Journal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences.
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13. 13
  Pettersson, M.; Hou, X.; Kuhn, M.; Wager, T. T.; Kauffman, G. W.; Verhoest, P. R. Quantitative assessment of the impact of fluorine substitution on P-glycoprotein (P-gp) mediated efflux, permeability, lipophilicity, and metabolic stability. J. Med. Chem. 2016, 59, 5284– 5296, DOI: 10.1021/acs.jmedchem.6b00027
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  13
  Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability
  Pettersson, Martin; Hou, Xinjun; Kuhn, Max; Wager, Travis T.; Kauffman, Gregory W.; Verhoest, Patrick R.
  Journal of Medicinal Chemistry (2016), 59 (11), 5284-5296CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Mol. wt. (MW) is a key parameter in design, and incorporation of fluorine is assocd. with a disproportionate increase in MW considering the van der Waals radius of fluorine vs. hydrogen. Herein we examine a large compd. data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-cor. mol. wt. (MWFC), where the mol. wt. of fluorine has been subtracted, was found to be a more relevant descriptor.
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14. 14
  Bott, F.; Field, L. D.; Sternhell, S. Steric effects. A study of a rationally designed system. J. Am. Chem. Soc. 1980, 102, 5618– 5626, DOI: 10.1021/ja00537a036
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  14
  Steric effects. A study of a rationally designed system
  Bott, Garry; Field, Leslie D.; Sternhell, Sever
  Journal of the American Chemical Society (1980), 102 (17), 5618-26CODEN: JACSAT; ISSN:0002-7863.
  The principles for the rational design of systems suitable for the study of steric effects are defined. A suitable mol. framework [6-(2-X-phenyl)-5-Y-1,1-dimethylindan, I] was synthesized and a study of internal rotation by dynamic NMR spectroscopy (DMNR) of 33 derivs., differing principally in the nature of the mol. fragment (X), showed that (i) for I,( Y = Me; X = halogen) the rotational barriers (ΔG⧧) increase smoothly and monotonically with the van der Waals radius of X (rx), which permits the estn. of effective rx for fragments of lower symmetry. (Ii) the rotational barriers are the sum of additive contributions, designated interference values (IH-X), which can be used to predict the rotational barriers in 2,2'-disubstituted biphenyls. (Iii) a simple geometrical parameter, apparent overlap (r*), which is related to the distortion of the framework in the transition state, is proposed and found to have an excellent linear correlation with the barrier to rotation in 2,2'-disubstituted biphenyls. (I.v.) this correlation can be used for a semiquant. estn. of rotational barriers in biaryls and other systems.
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15. 15
  (a) Lunazzi, L.; Mancinelli, M.; Mazzanti, A.; Lepri, S.; Ruzziconi, R.; Schlosser, M. Rotational barriers of biphenyls having heavy heteroatoms as ortho substituents: experimental and theoretical determination of steric effects. Org. Biomol. Chem. 2012, 10, 1847– 1855, DOI: 10.1039/c1ob06688a
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  (b) de Riggi, I.; Virgili, A.; de Moragas, M.; Jaime, C. Restricted rotation and NOE transfer: a conformational study of some substituted (9-anthry1)carbinol derivatives. J. Org. Chem. 1995, 60, 27– 31, DOI: 10.1021/jo00106a010
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  (c) Belot, V.; Farran, D.; Jean, M.; Albalat, M.; Vanthuyne, N.; Roussel, C. Steric scale of common substituents from rotational barriers of N-(o-substituted aryl)thiazoline-2-thione atropisomers. J. Org. Chem. 2017, 82, 10188– 10200, DOI: 10.1021/acs.joc.7b01698
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  15c
  Steric Scale of Common Substituents from Rotational Barriers of N-(o-Substituted aryl)thiazoline-2-thione Atropisomers
  Belot, Vincent; Farran, Daniel; Jean, Marion; Albalat, Muriel; Vanthuyne, Nicolas; Roussel, Christian
  Journal of Organic Chemistry (2017), 82 (19), 10188-10200CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A steric scale of 20 recurrent groups was established from comparison of rotational barriers on N-(o-substituted aryl)thiazoline-2-thione atropisomers. The resulting energy of activation ΔG⧺rot reflects the spatial requirement of the ortho substituent borne by the aryl moiety, electronic aspects and external parameters (temp. and solvent) generating negligible contributions. Concerning divergent rankings reported in the literature, the great sensitivity of this model allowed us to show unambiguously that a Me appears bigger than a chlorine and gave the following order in size: CN > OMe > OH. For the very bulky CF3 and iPr groups, constraints in the ground state decreased the expected ΔG⧺rot values resulting in a minimization of their apparent sizes.
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  Jagodzinska, M.; Huguenot, F.; Candiani, G.; Zanda, M. Assessing the bioisosterism of the trifluoromethyl group with a protease probe. ChemMedChem 2009, 4, 49– 51, DOI: 10.1002/cmdc.200800321
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  Assessing the bioisosterism of the trifluoromethyl group with a protease probe
  Jagodzinska, Monika; Huguenot, Florent; Candiani, Gabriele; Zanda, Matteo
  ChemMedChem (2009), 4 (1), 49-51CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Prepn. of barbiturates with MMPs inhibiting activities is described.
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17. 17
  Shaughnessy, M. J.; Harsanyi, A.; Li, J.; Bright, T.; Murphy, C. D.; Sandford, G. Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life. ChemMedChem 2014, 9, 733– 736, DOI: 10.1002/cmdc.201300490
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  Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S. Metabolism-guided drug design. MedChemComm 2013, 4, 631– 652, DOI: 10.1039/c2md20317k
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  Metabolism-guided drug design
  Stepan, Antonia F.; Mascitti, Vincent; Beaumont, Kevin; Kalgutkar, Amit S.
  MedChemComm (2013), 4 (4), 631-652CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  A review. Preclin. drug metab. studies play a key role in the lead identification and optimization process in drug discovery. Characterization of the metabolic pathways of new chem. entities is an integral part of drug discovery not only in optimizing clearance properties but also in eliminating potential safety concerns assocd. with the formation of protein and/or DNA-reactive metabolites. Metab. studies in early discovery have been used to identify metabolic soft spots leading to high metabolic instability, and also in the characterization of active metabolites. Availability of such information has aided in the rational design of compds. with increased resistance to metab. and overall improvements in oral pharmacokinetics and dose size. Mechanistic drug metab. studies have proven particularly invaluable in mitigating reactive metabolite risks, which can lead to mutagenicity, time-dependent inactivation of cytochrome P 450 enzymes and/or idiosyncratic adverse drug reactions. Characterization of stable conjugates derived from bioactivation of small mol. drug candidates provides indirect information on the structure of the reactive metabolite species, thereby providing insight into the bioactivation mechanism and hence a rationale on which to base subsequent chem. intervention strategies. This review will showcase case studies of metab.-guided drug design using literature and inhouse examples.
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  Dossetter, A. G. A matched molecular pair analysis of in vitro human microsomal metabolic stability measurements for methylene substitution or replacements - identification of those transforms more likely to have beneficial effects. MedChemComm 2012, 3, 1518– 1525, DOI: 10.1039/c2md20226c
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20. 20
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  (a) Ojima, I. Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies. J. Fluorine Chem. 2017, 198, 10– 23, DOI: 10.1016/j.jfluchem.2016.12.016
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  Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies
  Ojima, Iwao
  Journal of Fluorine Chemistry (2017), 198 (), 10-23CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
  This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to taxoid anticancer agents and their tumor-targeted drug delivery systems (TTDDSs) for medicinal chem. and chem. biol. studies. Novel 3'-difluorovinyltaxoids were strategically designed to block the metab. by cytochrome P 450, synthesized, and evaluated for their cytotoxicity against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines. 3'-Difluorovinyltaxoids exhibited impressive activities against these cancer cell lines. More significantly, a representative 3'-difluorovinyltaxoid exhibited 230-33,000 times higher potency than conventional anticancer drugs against cancer stem cell-enriched HCT-116 cell line. Studies on the mechanism of action (MOA) of these fluorotaxoids were performed by tubulin polymn. assay, morphol. anal. by electron microscopy (EM) and protein binding assays. Novel 19F NMR probes, BLT-F2 and BLT-S-F6, were designed by strategically incorporating fluorine, CF3 and CF3O groups into tumor-targeting drug conjugates. These 19F-probes were designed and synthesized to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time 19F NMR anal. Time-resolved 19F NMR study on probe BLT-F2 revealed a stepwise mechanism for the release of a fluorotaxoid, which might not be detected by other anal. methods. Probe BLT-S-F6 were very useful to study the stability and reactivity of the drug delivery system in human blood plasma by 19F NMR. The clean anal. of the linker stability and reactivity of drug conjugates in blood plasma by HPLC and 1H NMR is very challenging, but the use of 19F NMR and suitable 19F probes can provide a practical soln. to this problem.
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  (b) Kuznetsova, L.; Sun, L.; Chen, J.; Zhao, X.; Seitz, J.; Das, M.; Li, Y.; Veith, J. M.; Pera, P.; Bernacki, R. J.; Xia, S.; Horwitz, S. B.; Ojima, I. Synthesis and biological evaluation of novel 3′-difluorovinyl toxoids. J. Fluorine Chem. 2012, 143, 177– 188, DOI: 10.1016/j.jfluchem.2012.07.007
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  Synthesis and biological evaluation of novel 3'-difluorovinyl taxoids
  Kuznetsova, Larissa; Sun, Liang; Chen, Jin; Zhao, Xianrui; Seitz, Joshua; Das, Manisha; Li, Yuan; Veith, Jean M.; Pera, Paula; Bernacki, Ralph J.; Xia, Shujun; Horwitz, Susan B.; Ojima, Iwao
  Journal of Fluorine Chemistry (2012), 143 (), 177-188CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
  A series of 3'-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metab. by cytochrome P 450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3'-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel. Structure-activity relationship study shows the crit. importance of the C2 modifications on the activity against MDR cancer cell line, while the C10 modifications have a rather minor effect on the potency with some exceptions. The effect of the C2 modifications on potency against MCF7 cell line increases in the following order: H < F < Cl < N3. Among the twenty five 3'-difluorovinyl taxoids evaluated, eight taxoids exhibited less than 100 pM IC50 values against MCF7 cell line. Difluorovinyl taxoids induced GTP-independent tubulin polymn. much faster than paclitaxel. Then, the resulting microtubules were stable to Ca2+-induced depolymn., indicating strong stabilization of microtubules. Mol. modeling study indicated that a difluorovinyl taxoid binds to β-tubulin in a manner that is consistent with the REDOR-Taxol structure. The difluorovinyl group appears to mimic the isobutenyl group to some extent, but with very different electronic property, which may account for the unique activities of difluorovinyl taxoids.
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  .
  (c) Ehrlichová, M.; Ojima, I.; Chen, J.; Václavíková, R.; Němcová-Fürstová, V.; Vobořilová, J.; Šimek, P.; Horský, S.; Souček, P.; Kovář, J.; Brabec, M.; Gut, I. Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 2012, 385, 1035– 1048, DOI: 10.1007/s00210-012-0785-4
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  Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells
  Ehrlichova, Marie; Ojima, Iwao; Chen, Jin; Vaclavikova, Radka; Nemcova-Fuerstova, Vlasta; Voborilova, Jana; Simek, Petr; Horsky, Stanislav; Soucek, Pavel; Kovar, Jan; Brabec, Marek; Gut, Ivan
  Naunyn-Schmiedeberg's Archives of Pharmacology (2012), 385 (10), 1035-1048CODEN: NSAPCC; ISSN:0028-1298. (Springer)
  Resistance of tumors to taxanes causes chemotherapy failure in numerous patients. Resistance is partly due to the low tumor uptake of taxanes and their rapid metab. Structural modifications of taxanes can reduce their P-glycoprotein-related efflux or decrease metab. and consequently increase taxane efficiency. This study compared cytotoxicity and effects of the cell cycle, transport and metab. of novel taxanes SB-T-1102, SB-T-1103, SB-T-1214 and SB-T-1216, fluorinated SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN5109 with paclitaxel in paclitaxel-sensitive (MDA-MB-435) and paclitaxel-resistant (NCI/ADR-RES) human cancer cells. We have shown before that NCI/ADR-RES cells were 1,000-fold less sensitive to paclitaxel than MDA-MB-435 cells in correspondence to P-glycoprotein overexpression and up to 20-fold lower uptake of the drug in the resistant cells. The uptake of novel taxanes was 1.2 to 3.8 times lower than that of paclitaxel in the MDA-MB-435 cells, but 1.5 to 6.5 times higher in NCI/ADR-RES cells. NCI/ADR-RES cells were correspondingly only 2- to 6.6-fold less sensitive than the MDA-MB-435 cells to novel taxanes. Both cell lines showed minimal metab. of the novel taxanes which was therefore not responsible for their different sensitivity, the obsd. differences in their individual efficiency and higher effects than paclitaxel. All novel taxanes caused G2/M block of the cell cycle similar to paclitaxel, but lower at concns. by order of magnitude. Thus, structural modifications of taxanes resulting in their decreased P-glycoprotein-related transport probably caused their higher efficiency than paclitaxel in multidrug-resistant NCI/ADR-RES tumor cells.
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22. 22
  Mascitti, V.; Stevens, B. D.; Choi, C.; McClure, K. F.; Guimarães, C. R. W.; Farley, K. A.; Munchhof, M. J.; Robinson, R. P.; Futatsugi, K.; Lavergne, S. Y.; Lefker, B.; Cornelius, A. P.; Bonin, P. D.; Kalgutkar, A. S.; Sharma, R.; Chen, Y. Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor. Bioorg. Med. Chem. Lett. 2011, 21, 1306– 1309, DOI: 10.1016/j.bmcl.2011.01.088
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  Barnes-Seeman, D.; Beck, J.; Springer, C. Fluorinated compounds in medicinal chemistry: recent applications, synthetic advances and matched-pair analysis. Curr. Top. Med. Chem. 2014, 14, 855– 864, DOI: 10.2174/1568026614666140202204242
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  Fluorinated Compounds in Medicinal Chemistry: Recent Applications, Synthetic Advances and Matched-Pair Analyses
  Barnes-Seeman, David; Beck, Jeremy; Springer, Clayton
  Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 14 (7), 855-864CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
  A review. In recent years, several new fluorinated functional groups have been employed in medicinal chem. This review will highlight some recent developments in this area. We draw attention to useful synthetic advances for the installation of fluorine-contg. groups. In addn., we examine the application of some fluorinated functional groups that have recently been gaining popularity in drug discovery. We use matched-pair anal. to assemble aggregate data on the impact on potency of one of these groups, pentafluorosulfanyl, as compared to trifluoromethyl. We further used matchedpair anal. to identify some interesting effects on in vitro ADME properties of replacing H by F on certain moieties.
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24. 24
  Barnes-Seeman, D.; Jain, M.; Bell, L.; Ferreira, S.; Cohen, S.; Chen, X.-H.; Amin, J.; Snodgrass, B.; Hatsis, P. Metabolically stable tert-butyl replacement. ACS Med. Chem. Lett. 2013, 4, 514– 516, DOI: 10.1021/ml400045j
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  Metabolically Stable tert-Butyl Replacement
  Barnes-Seeman, David; Jain, Monish; Bell, Leslie; Ferreira, Suzie; Cohen, Scott; Chen, Xiao-Hui; Amin, Jakal; Snodgrass, Brad; Hatsis, Panos
  ACS Medicinal Chemistry Letters (2013), 4 (6), 514-516CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  Susceptibility to metab. is a common issue with the tert-Bu group on compds. of medicinal interest. The authors demonstrate an approach of removing all the fully Sp3 C-Hs from a tert-Bu group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-contg. analogs had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-contg. counterparts.
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25. 25
  Westphal, M. V.; Wolfstädter, B. T.; Plancher, J.-M.; Gatfield, J.; Carreira, E. M. Evaluation of tert-butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities. ChemMedChem 2015, 10, 461– 469, DOI: 10.1002/cmdc.201402502
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  Evaluation of tert-Butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities
  Westphal, Matthias V.; Wolfstaedter, Bernd T.; Plancher, Jean-Marc; Gatfield, John; Carreira, Erick M.
  ChemMedChem (2015), 10 (3), 461-469CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The tert-Bu group is a common motif in medicinal chem. Its incorporation into bioactive compds. is often accompanied by unwanted property modulation, such as increased lipophilicity and decreased metabolic stability. Several alternative substituents are available for the drug discovery process. Herein, physicochem. data of two series of drug analogs of bosentan and vercirnon are documented as part of a comparative study of tert-Bu, pentafluorosulfanyl, trifluoromethyl, bicyclo[1.1.1]pentyl, and cyclopropyl-trifluoromethyl substituents.
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26. 26
  Chao, Q.; Sprankle, K. G.; Grotzfeld, R. M.; Lai, A. G.; Carter, T. A.; Velasco, A. M.; Gunawardane, R. N.; Cramer, M. D.; Gardner, M. F.; James, J.; Zarrinkar, P. P.; Patel, H. K.; Bhagwat, S. S. Identification of N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo-[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor. J. Med. Chem. 2009, 52, 7808– 7816, DOI: 10.1021/jm9007533
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  Sanga, M.; James, J.; Marini, J.; Gammon, G.; Hale, C.; Li, J. An open-label, single-dose, phase I study of the absorption, metabolism, and excretion of quizartinib, a highly selective and potent FLT3 tyrosine kinase inhibitor, in healthy male subjects, for the treatment of acute myeloid leukemia. Xenobiotica 2017, 47, 856– 869, DOI: 10.1080/00498254.2016.1217100
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  Liu, G.; Abraham, S.; Liu, X.; Xu, S.; Rooks, A. M.; Nepomuceno, R.; Dao, A.; Brigham, D.; Gitnick, D.; Insko, D. E.; Gardner, M. F.; Zarrinkar, P. P.; Christopher, R.; Belli, B.; Armstrong, R. C.; Holladay, M. W. Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 3436– 3441, DOI: 10.1016/j.bmcl.2015.07.023
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  Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors
  Liu, Gang; Abraham, Sunny; Liu, Xing; Xu, Shimin; Rooks, Allison M.; Nepomuceno, Ron; Dao, Alan; Brigham, Daniel; Gitnick, Dana; Insko, Darren E.; Gardner, Michael F.; Zarrinkar, Patrick P.; Christopher, Ron; Belli, Barbara; Armstrong, Robert C.; Holladay, Mark W.
  Bioorganic & Medicinal Chemistry Letters (2015), 25 (17), 3436-3441CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Based on a putative binding mode of quizartinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clin. development, the authors have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compd. I in tumor xenograft model for further preclin. development.
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29. 29
  Sebhat, I. K.; Franklin, C.; Lo, M. M.-C.; Chen, D.; Jewell, J. P.; Miller, R.; Pang, J.; Palyha, O.; Kan, Y.; Kelly, T. M.; Guan, X.-M.; Marsh, D. J.; Kosinski, J. A.; Metzger, J. M.; Lyons, K.; Dragovic, J.; Guzzo, P. R.; Henderson, A. J.; Reitman, M. L.; Nargund, R. P.; Wyvratt, M. J.; Lin, L. S. Discovery of MK-5046, a potent, selective bombesin receptor subtype-3 agonist for the treatment of obesity. ACS Med. Chem. Lett. 2011, 2, 43– 47, DOI: 10.1021/ml100196d
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  Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity
  Sebhat, Iyassu K.; Franklin, Christopher; Lo, Michael M.-C.; Chen, David; Jewell, James P.; Miller, Randy; Pang, Jianmei; Palyha, Oksana; Kan, Yanqing; Kelly, Theresa M.; Guan, Xiao-Ming; Marsh, Donald J.; Kosinski, Jennifer A.; Metzger, Joseph M.; Lyons, Kathryn; Dragovic, Jasminka; Guzzo, Peter R.; Henderson, Alan J.; Reitman, Marc L.; Nargund, Ravi P.; Wyvratt, Matthew J.; Lin, Linus S.
  ACS Medicinal Chemistry Letters (2011), 2 (1), 43-47CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  We report the development and characterization of compd. 22 (MK-5046), a potent, selective small mol. agonist of BRS-3 (bombesin receptor subtype-3). In pharmacol. testing using diet-induced obese mice, compd. 22 caused mechanism-based, dose-dependent redns. in food intake and body wt.
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30. 30
  Furet, P.; Guagnano, V.; Fairhurst, R. A.; Imbach-Weese, P.; Bruce, I.; Knapp, M.; Fritsch, C.; Blasco, F.; Blanz, J.; Aichholz, R.; Hamon, J.; Fabbro, D.; Caravatti, G. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett. 2013, 23, 3741– 3748, DOI: 10.1016/j.bmcl.2013.05.007
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  Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation
  Furet, Pascal; Guagnano, Vito; Fairhurst, Robin A.; Imbach-Weese, Patricia; Bruce, Ian; Knapp, Mark; Fritsch, Christine; Blasco, Francesca; Blanz, Joachim; Aichholz, Reiner; Hamon, Jacques; Fabbro, Doriano; Caravatti, Giorgio
  Bioorganic & Medicinal Chemistry Letters (2013), 23 (13), 3741-3748CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Phosphatidylinositol-3-kinase α (PI3Kα) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2-aminothiazole compds. in inhibiting PI3Kα, a medicinal chem. program has led to the discovery of the clin. candidate NVP-BYL719 I.
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31. 31
  (a) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A survey of the role of noncovalent sulfur interactions in drug design. J. Med. Chem. 2015, 58, 4383– 4438, DOI: 10.1021/jm501853m
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  A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design
  Beno, Brett R.; Yeung, Kap-Sun; Bartberger, Michael D.; Pennington, Lewis D.; Meanwell, Nicholas A.
  Journal of Medicinal Chemistry (2015), 58 (11), 4383-4438CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. Electron deficient, bivalent sulfur atoms have two areas of pos. electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramol. interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a mol. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramol. hydrogen-bonding interaction, appears to be underappreciated by the medicinal chem. community. In this Perspective, we discuss the theor. basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and org. synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermol. interactions between ligand C-S σ* orbitals and proteins are illustrated.
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  (b) Zhang, X.; Gong, Z.; Li, J.; Lu, T. Intermolecular sulfur···oxygen interactions: theoretical and statistical investigations. J. Chem. Inf. Model. 2015, 55, 2138– 2153, DOI: 10.1021/acs.jcim.5b00177
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  31b
  Intermolecular Sulfur···Oxygen Interactions: Theoretical and Statistical Investigations
  Zhang, Xuejin; Gong, Zhen; Li, Jian; Lu, Tao
  Journal of Chemical Information and Modeling (2015), 55 (10), 2138-2153CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
  Intermol. S···O interactions are very common and are important in biol. systems, but until recently, the presence of these contacts in protein-ligand systems largely depended on serendipitous discovery instead of rational design. Here we provide insight into the phenomenon of intermol. S···O contacts by focusing on three sulfur-contg. arom. rings. Quantum mechanics is employed to characterize the strength and directionality of the S···O interactions and to det. their energy dependence on their geometric parameters. Protein Data Bank mining is performed to systematically det. the occurrence and geometry of intermol. S···O interactions, and several representative examples are discussed. Three typical cases are investigated using a combined quantum mechanics/mol. mechanics approach to demonstrate the potential of these interactions in improving binding affinities and physiochem. properties. Overall, our work elucidates the structures and energy features of intermol. S···O interactions and addresses their use in mol. design.
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32. 32
  Rowbottom, M. W.; Faraoni, R.; Chao, Q.; Campbell, B. T.; Lai, A. G.; Setti, E.; Ezawa, M.; Sprankle, K. G.; Abraham, S.; Tran, L.; Struss, B.; Gibney, M.; Armstrong, R. C.; Gunawardane, R. N.; Nepomuceno, R. R.; Valenta, I.; Hua, H.; Gardner, M. F.; Cramer, M. D.; Gitnick, D.; Insko, D. E.; Apuy, J. L.; Jones-Bolin, S.; Ghose, A. K.; Herbertz, T.; Ator, M. A.; Dorsey, B. D.; Ruggeri, B.; Williams, M.; Bhagwat, S.; James, J.; Holladay, M. W. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E. J. Med. Chem. 2012, 55, 1082– 1105, DOI: 10.1021/jm2009925
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33. 33
  Pettersson, M.; Johnson, D. S.; Humphrey, J. M.; Butler, T. W.; am Ende, C. W.; Fish, B. A.; Green, M. E.; Kauffman, G. W.; Mullins, P. B.; O’Donnell, C. J.; Stepan, A. F.; Stiff, C. M.; Subramanyam, C.; Tran, T. P.; Cooper Vetelino, B.; Yang, E.; Xie, L.; Bales, K. R.; Pustilnik, L. R.; Steyn, S. J.; Wood, K. M.; Verhoest, P. R. Design of pyridopyrazine-1,6-dione γ-secretase modulators that align potency, MDR efflux ratio, and metabolic stability. ACS Med. Chem. Lett. 2015, 6, 596– 601, DOI: 10.1021/acsmedchemlett.5b00070
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  Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability
  Pettersson, Martin; Johnson, Douglas S.; Humphrey, John M.; Butler, Todd W.; am Ende, Christopher W.; Fish, Benjamin A.; Green, Michael E.; Kauffman, Gregory W.; Mullins, Patrick B.; O'Donnell, Christopher J.; Stepan, Antonia F.; Stiff, Cory M.; Subramanyam, Chakrapani; Tran, Tuan P.; Vetelino, Beth Cooper; Yang, Eddie; Xie, Longfei; Bales, Kelly R.; Pustilnik, Leslie R.; Steyn, Stefanus J.; Wood, Kathleen M.; Verhoest, Patrick R.
  ACS Medicinal Chemistry Letters (2015), 6 (5), 596-601CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochem. properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp3-character. The lead compd. I (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust redns. of brain Aβ42 and Aβ40 were obsd. in a guinea pig time-course expt.
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34. 34
  Mukherjee, P.; Pettersson, M.; Dutra, J. K.; Xie, L.; am Ende, C. W. Trifluoromethyl oxetanes: synthesis and evaluation as a tert-butyl isostere. ChemMedChem 2017, 12, 1574– 1577, DOI: 10.1002/cmdc.201700333
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  Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl Isostere
  Mukherjee, Paramita; Pettersson, Martin; Dutra, Jason K.; Xie, Longfei; am Ende, Christopher W.
  ChemMedChem (2017), 12 (19), 1574-1577CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The synthesis of new trifluoromethyl oxetanes such as I [R = 4-CO2HC6H4, 2-MeOC6H4CH2, 5-CO2Et-2-thienyl, etc.] was developed using Corey-Chaykovsky epoxidn./ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displayed a broad substrate scope. A limitation to the epoxidn./ring expansion was obsd. when attempting to use a more sterically encumbered aryl trifluoromethyl ketone, the intermediate epoxide, 2-(trifluoromethyl)-2-(2,4,6-trimethylphenyl)oxirane was isolated. The trifluoromethyl oxetane was also evaluated as a tert-Bu isostere in the context of the γ-secretase modulator (GSM) program. The trifluoromethyl oxetane-contg. GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-Bu GSM analog was demonstrated, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-Bu isostere.
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35. 35
  (a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2005, 48, 141– 151, DOI: 10.1021/jm0493156
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  35a
  (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
  Kim, Dooseop; Wang, Liping; Beconi, Maria; Eiermann, George J.; Fisher, Michael H.; He, Huaibing; Hickey, Gerard J.; Kowalchick, Jennifer E.; Leiting, Barbara; Lyons, Kathryn; Marsilio, Frank; McCann, Margaret E.; Patel, Reshma A.; Petrov, Aleksandr; Scapin, Giovanna; Patel, Sangita B.; Roy, Ranabir Sinha; Wu, Joseph K.; Wyvratt, Matthew J.; Zhang, Bei B.; Zhu, Lan; Thornberry, Nancy A.; Weber, Ann E.
  Journal of Medicinal Chemistry (2005), 48 (1), 141-151CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (I) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclin. species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of I, was selected for development as a potential new treatment for type 2 diabetes.
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  .
  (b) Kim, D.; Kowalchick, J.E.; Edmondson, S. D.; Mastracchio, A.; Xu, J.; Eiermann, G. J.; Leiting, B.; Wu, J. K.; Pryor, K. D.; Patel, R. A.; He, H.; Lyons, K. A.; Thornberry, N. A.; Weber, A. E. Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate). Bioorg. Med. Chem. Lett. 2007, 17, 3373– 3377, DOI: 10.1016/j.bmcl.2007.03.098
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  (c) Thornberry, N. A.; Weber, A. E. Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Curr. Top. Med. Chem. 2007, 7, 557– 568, DOI: 10.2174/156802607780091028
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  Discovery of JANUVIA (sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
  Thornberry, Nancy A.; Weber, Ann E.
  Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2007), 7 (6), 557-568CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
  A review. The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclin. validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compds. inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclin. species. Indeed, the obsd. toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chem. efforts focused on identifying a highly selective DPP-4 inhibitor for clin. development. Initial work in an α-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective β-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivs. were prepd., culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclin. species. Optimization of this series led to the discovery of JANUVIA (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.
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36. 36
  Mayer, S. C.; Kreft, A. F.; Harrison, B.; Abou-Gharbia, M.; Antane, M.; Aschmies, S.; Atchison, K.; Chlenov, M.; Cole, D. C.; Comery, T.; Diamantidis, G.; Ellingboe, J.; Fan, K.; Galante, R.; Gonzales, C.; Ho, D. M.; Hoke, M. E.; Hu, Y.; Huryn, D.; Jain, U.; Jin, M.; Kremer, K.; Kubrak, D.; Lin, M.; Lu, P.; Magolda, R.; Martone, R.; Moore, W.; Oganesian, A.; Pangalos, M. N.; Porte, A.; Reinhart, P.; Resnick, L.; Riddell, D. R.; Sonnenberg-Reines, J.; Stock, J. R.; Sun, S.-C.; Wagner, E.; Wang, T.; Woller, K.; Xu, Z.; Zaleska, M. M.; Zeldis, J.; Zhang, M.; Zhou, H.; Jacobsen, J. S. Discovery of begacestat, a notch-1-sparing γ-secretase inhibitor for the treatment of Alzheimer’s disease. J. Med. Chem. 2008, 51, 7348– 7351, DOI: 10.1021/jm801252w
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  Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease
  Mayer, Scott C.; Kreft, Anthony F.; Harrison, Boyd; Abou-Gharbia, Magid; Antane, Madelene; Aschmies, Suzan; Atchison, Kevin; Chlenov, Michael; Cole, Derek C.; Comery, Thomas; Diamantidis, George; Ellingboe, John; Fan, Kristi; Galante, Rocco; Gonzales, Cathleen; Ho, Douglas M.; Hoke, Molly E.; Hu, Yun; Huryn, Donna; Jain, Uday; Jin, Mei; Kremer, Kenneth; Kubrak, Dennis; Lin, Melissa; Lu, Peimin; Magolda, Ron; Martone, Robert; Moore, William; Oganesian, Aram; Pangalos, Menelas N.; Porte, Alex; Reinhart, Peter; Resnick, Lynn; Riddell, David R.; Sonnenberg-Reines, June; Stock, Joseph R.; Sun, Shaiu-Ching; Wagner, Erik; Wang, Ting; Woller, Kevin; Xu, Zheng; Zaleska, Margaret M.; Zeldis, Joseph; Zhang, Minsheng; Zhou, Hua; Jacobsen, J. Steven
  Journal of Medicinal Chemistry (2008), 51 (23), 7348-7351CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Aβ in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile Me groups in 9 to trifluoromethyl groups afforded the more stable analog 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.
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37. 37
  Floyd, D. M.; Stein, P.; Wang, Z.; Liu, J.; Castro, S.; Clark, J. A.; Connelly, M.; Zhu, F.; Holbrook, G.; Matheny, A.; Sigal, M. S.; Min, J.; Dhinakaran, R.; Krishnan, S.; Bashyum, S.; Knapp, S.; Guy, R. K. Hit-to-lead studies for the antimalarial tetrahydroisoquinolone carboxanilides. J. Med. Chem. 2016, 59, 7950– 7962, DOI: 10.1021/acs.jmedchem.6b00752
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  Selnick, H. G.; Liverton, N. J.; Baldwin, J. J.; Butcher, J. W.; Claremon, D. A.; Elliott, J. M.; Freidinger, R. M.; King, S. A.; Libby, B. E.; McIntyre, C. J.; Pribush, D. A.; Remy, D. C.; Smith, G. R.; Tebben, A. J.; Jurkiewicz, N. K.; Lynch, J. J.; Salata, J. J.; Sanguinetti, M. C.; Siegl, P. K. S.; Slaughter, D. E.; Vyas, K. Class III antiarrhythmic activity in vivo by selective blockade of the slowly activating cardiac delayed rectifier potassium current I_Ks by (R)-2-(2,4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide. J. Med. Chem. 1997, 40, 3865– 3868, DOI: 10.1021/jm970517u
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  (a) Tohnishi, M.; Nishimatsu, T.; Motoba, K.; Hirooka, T.; Seo, A. Development of a novel insecticide, flubendiamide. J. Pestic. Sci. 2010, 35, 490– 491, DOI: 10.1584/jpestics.J10-06
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  Development of a novel insecticide, flubendiamide
  Tohnishi, Masanori; Nishimatsu, Tetsuyoshi; Motoba, Kazuhiko; Hirooka, Takashi; Akira, Seo
  Journal of Pesticide Science (Tokyo, Japan) (2010), 35 (4), 490-491, 508-515CODEN: JPSTCF; ISSN:1348-589X. (Pesticide Science Society of Japan)
  Flubendiamide, a novel class insecticide possessing a unique chem. structure, was discovered by Nihon Nohyaku Co., Ltd., and was registered in Japan in 2007 under the trade name of Phoenix WDG. The compd. is not only the first example of 1,2-benzenedicarboxamide insecticides but also the first practical synthetic insecticide with a mode of action as an activator of ryanodine receptors. It shows high and selective activity against lepidopterous insect pests, which leads to excellent efficacy in the field and excellent safety against non-target organisms, including various beneficial arthropods and natural enemies. These properties suggested the suitability of flubendiamide for integrated pest management (IPM) programs.
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  Broflanilide: A meta-diamide insecticide with a novel mode of action
  Nakao, Toshifumi; Banba, Shinichi
  Bioorganic & Medicinal Chemistry (2016), 24 (3), 372-377CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  A review. Broflanilide is a meta-diamide [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamide] that exhibits high larvicidal activity against Spodoptera litura. It has been suggested that broflanilide is metabolized to desmethyl-broflanilide and that it acts as a noncompetitive resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor antagonist. The binding site of desmethyl-broflanilide was demonstrated to be distinct from that of conventional noncompetitive antagonists such as fipronil. It has been proposed that the site of action for desmethyl-broflanilide is close to G336 in the M3 region of the Drosophila RDL GABA receptor. However, although the site of action for desmethyl-broflanilide appears to overlap with that of macrocyclic lactones, different modes of actions have been demonstrated for desmethyl-broflanilide and the macrocyclic lactones. The mechanisms underlying the high selectivity of meta-diamides are also discussed in this review. Broflanilide is expected to become a prominent insecticide because it is effective against pests with resistance to cyclodienes and fipronil.
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40. 40
  Swaminathan, S.; Siddiqui, A. U.; Pinkerton, F. D.; Gerst, N.; Wilson, W. K.; Schroepfer, G. J. Inhibitors of sterol synthesis: 3β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5α-cholestan-15-one, an analog of a potent hypocholesterolemic agent in which its major metabolism is blocked. Biochem. Biophys. Res. Commun. 1994, 201, 168– 173, DOI: 10.1006/bbrc.1994.1684
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  Lepri, S.; Goracci, L.; Valeri, A.; Cruciani, G. Metabolism study and biological evaluation of bosentan derivatives. Eur. J. Med. Chem. 2016, 121, 658– 670, DOI: 10.1016/j.ejmech.2016.06.006
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  Metabolism study and biological evaluation of bosentan derivatives
  Lepri, Susan; Goracci, Laura; Valeri, Aurora; Cruciani, Gabriele
  European Journal of Medicinal Chemistry (2016), 121 (), 658-670CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
  Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P 450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogs are often designed to block the major sites of metab. In this paper bosentan analogs were synthesized, and their metab. and biol. activity were evaluated. All synthesized compds. showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
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  (a) Thangavelu, B.; Bhansali, P.; Viola, R. E. Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors. Bioorg. Med. Chem. 2015, 23, 6622– 6631, DOI: 10.1016/j.bmc.2015.09.017
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  Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease
  Thangavelu, Bharani; Mutthamsetty, Vinay; Wang, Qinzhe; Viola, Ronald E.
  Bioorganic & Medicinal Chemistry (2017), 25 (3), 870-885CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  Canavan disease is a fatal neurol. disorder caused by defects in the metab. of N-acetyl-L-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA obsd. in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-assocd. enzyme responsible for the synthesis of NAA, aspartate N-acetyltransferase (ANAT), has recently been purified and examd. (Wang et al., Prot Expr Purif. 2016;119:11). With the availability, for the first time, of a stable and sol. form of ANAT the authors can now report the identification of initial inhibitors against this biosynthetic enzyme, obtained from the screening of several focused compd. libraries. Two core structures of these moderate binding compds. have subsequently been optimized, with the most potent inhibitors in these series possessing sub-micromolar inhibition consts. (Ki values) against ANAT. Slowing the prodn. of NAA via the inhibition of ANAT will lower the elevated levels of this metabolite and can potentially serve as a treatment option to moderate the symptoms of Canavan disease.
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  Kees, K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl)(trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem. 1996, 39, 3920– 3928, DOI: 10.1021/jm960444z
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  (a) Rose, T. E.; Morisseau, C.; Liu, J.-Y.; Inceoglu, B.; Jones, P. D.; Sanborn, J. R.; Hammock, B. D. 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain. J. Med. Chem. 2010, 53, 7067– 7075, DOI: 10.1021/jm100691c
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  1-Aryl-3-(1-acylpiperidin-4-yl)urea Inhibitors of Human and Murine Soluble Epoxide Hydrolase: Structure-Activity Relationships, Pharmacokinetics, and Reduction of Inflammatory Pain
  Rose, Tristan E.; Morisseau, Christophe; Liu, Jun-Yan; Inceoglu, Bora; Jones, Paul D.; Sanborn, James R.; Hammock, Bruce D.
  Journal of Medicinal Chemistry (2010), 53 (19), 7067-7075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine sol. epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea showed a 7-fold increase in potency, a 65-fold increase in Cmax, and a 3300-fold increase in AUC over its adamantane analog 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea. This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mech. withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.
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  .
  (b) Lee, K. S. S.; Liu, J.-Y.; Wagner, K. M.; Pakhomova, S.; Dong, H.; Morisseau, C.; Fu, S. H.; Yang, J.; Wang, P.; Ulu, A.; Mate, C. A.; Nguyen, L. V.; Hwang, S. H.; Edin, M. L.; Mara, A. A.; Wulff, H.; Newcomer, M. E.; Zeldin, D. C.; Hammock, B. D. Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy. J. Med. Chem. 2014, 57, 7016– 7030, DOI: 10.1021/jm500694p
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  44b
  Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy
  Lee, Kin Sing Stephen; Liu, Jun-Yan; Wagner, Karen M.; Pakhomova, Svetlana; Dong, Hua; Morisseau, Christophe; Fu, Samuel H.; Yang, Jun; Wang, Peng; Ulu, Arzu; Mate, Christina A.; Nguyen, Long V.; Hwang, Sung Hee; Edin, Matthew L.; Mara, Alexandria A.; Wulff, Heike; Newcomer, Marcia E.; Zeldin, Darryl C.; Hammock, Bruce D.
  Journal of Medicinal Chemistry (2014), 57 (16), 7016-7030CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of sol. epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, the authors describe a series of newly synthesized sEH inhibitors I [R1 = 4-CF3C6H4, 4-CF3OC6H4; (CF3)2CFC6H4, etc.; R2 = MeCO, MeCH2CO, MeCH2CH2CO, etc.] with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better phys. properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
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45. 45
  Atouioual, B.; Hagmann, L.; Jung, P. M. J.; Lamy, E.; Winkler, T. Atropisomerism about a heptafluoroisopropyl to aryl bond in 5-amino-4-heptafluoroisopropyl indazole. Tetrahedron Lett. 2008, 49, 5403– 5404, DOI: 10.1016/j.tetlet.2008.07.006
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46. 46
  (a) Dieckhaus, C. M.; Thompson, C. D.; Roller, S. G.; Macdonald, T. L. Mechanisms of idiosyncratic drug reactions: the case of felbamate. Chem.-Biol. Interact. 2002, 142, 99– 117, DOI: 10.1016/S0009-2797(02)00057-1
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  Mechanisms of idiosyncratic drug reactions: the case of Felbamate
  Dieckhaus, Christine M.; Thompson, Charles D.; Roller, Shane G.; MacDonald, Timothy L.
  Chemico-Biological Interactions (2002), 142 (1-2), 99-117CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)
  A review. Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence, and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicol. outcome. As the name implies, IDR are unpredictable and often result in the post-marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include Trovafloxacin, Zileuton, Troglitazone, Tolcapone, and Felbamate. To date there exists no pre-clin. model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, the authors have studied the IDR assocd. with a model compd., Felbamate. The studies with Felbamate are consistent with the theory that compds. which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In addn., the data suggest that under normal physiol. conditions glutathione plays a protective role in preventing IDR during Felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clin. studies with Felbamate have been able to demonstrate an assocn. between reactive metabolite formation and a clin. relevant toxicity; however, addnl. research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.
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  .
  (b) Kapetanovic, I. M.; Torchin, C. D.; Strong, J. M.; Yonekawa, W. D.; Lu, C.; Li, A. P.; Dieckhaus, C. M.; Santos, W. L.; Macdonald, T. L.; Sofia, R. D.; Kupferberg, H. J. Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro. Chem.-Biol. Interact. 2002, 142, 119– 134, DOI: 10.1016/S0009-2797(02)00058-3
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  46b
  Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro
  Kapetanovic, Izet M.; Torchin, Cynthia D.; Strong, John M.; Yonekawa, Wayne D.; Lu, Chuang; Li, Albert P.; Dieckhaus, Christine M.; Santos, Webster L.; MacDonald, Timothy L.; Sofia, R. Duane; Kupferberg, Harvey J.
  Chemico-Biological Interactions (2002), 142 (1-2), 119-134CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)
  Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia assocd. with its use. It was proposed that a bioactivation of FBM leading to formation of α,β-unsatd. aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities assocd. with the parent drug. Other members of this class of compds., acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examd. effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metab. and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metab. of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concns. of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as obsd. with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metab. and/or metab. of other endogenous or exogenous compds. and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with crit. cellular macromols. or indirect interference with cellular detoxification mechanisms.
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  (c) Popović, M.; Nierkens, S.; Pieters, R.; Uetrecht, J. Investigating the role of 2-phenylpropenal in felbamate-induced idiosyncratic drug reactions. Chem. Res. Toxicol. 2004, 17, 1568– 1576, DOI: 10.1021/tx0498197
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  Parker, R. J.; Hartman, N. R.; Roecklein, B. A.; Mortko, H.; Kupferberg, H. J.; Stables, J.; Strong, J. M. Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by post-mitochondrial suspensions. Chem. Res. Toxicol. 2005, 18, 1842– 1848, DOI: 10.1021/tx050130r
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48. 48
  (a) Kupferberg, H. J.; Macdonald, T. L.; Dieckhaus, C. M.; Perhach, J. L.; Sofia, R. D. Fluorofelbamate: pharmacodynamic and metabolic profile of a potent anticonvulsant. Epilepsia 2000, 41 (Suppl 7), 214
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  (b) Mazarati, A. M.; Sofia, R. D.; Wasterlain, C. G. Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus. Seizure 2002, 11, 423– 430, DOI: 10.1053/seiz.2002.0677
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  Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus
  Mazarati Andrey M; Sofia R Duane; Wasterlain Claude G
  Seizure (2002), 11 (7), 423-30 ISSN:1059-1311.
  PURPOSE: To examine the seizure-protective properties of fluorofelbamate, a felbamate analog, on acute and chronic seizures in an experimental model of self-sustaining status epilepticus (SSSE). METHODS: SSSE was induced by stimulation of the perforant path for 30 min (PPS) through chronically implanted electrodes in free-running adult male Wistar rats. Fluorofelbamate was injected intravenously (i.v.) either 10 min, or 40 min after SSSE induction. Seizure and spike profiles were analyzed off-line. RESULTS: Fluorofelbamate injected during the early stages of SSSE (10 min after the end of PPS), shortened the duration of seizures in a dose-dependent manner. While a dose of 50 mg kg(-1) was ineffective, 100 and 200 mg kg(-1) reduced cumulative seizure time from 393 +/- 10 min to 15 +/- 8 min and 2.4 +/- 0.5 min respectively. Administration of fluorofelbamate (200 and 300 mg kg (-1)) at a late stage of SSSE, which is refractory to treatment with conventional anticonvulsants, also significantly attenuated seizures. Acute fluorofelbamate treatment (200 mg kg(-1) 10 min after PPS) significantly decreased the frequency of spontaneous seizures which follow SSSE after a 'latent' interval. Moreover, in contrast to control animals, fluorofelbamate-treated rats showed regression of spontaneous seizures, and an apparent remission of epilepsy within 2 months after SSSE. CONCLUSIONS: Acute treatment of SSSE with fluorofelbamate showed strong anticonvulsant effects even during the late stages of SSSE. In this model, it also displayed antiepileptogenic properties: it reduced the severity of chronic epilepsy after SSSE and lead to apparent remissions of that epilepsy.
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49. 49
  (a) Roecklein, B. A.; Sacks, H. J.; Mortko, H.; Stables, J. Fluorofelbamate. Neurotherapeutics 2007, 4, 97– 101, DOI: 10.1016/j.nurt.2006.11.015
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  Fluoro0felbamate
  Roecklein, Bryan A.; Sacks, Harry J.; Mortko, Henry; Stables, James
  Neurotherapeutics (2007), 4 (1), 97-101CODEN: NEURNV; ISSN:1933-7213. (Elsevier)
  A review. The incidence of refractory seizures has remained at 30-40%, even with the approval of nine new anticonvulsants over the past 12 years. In attempts to reduce seizure frequency and severity, physicians routinely resort to combining two or more anticonvulsants, ideally with different mechanisms of action. These combinatorial therapies are difficult to administer for both patient and caregiver and often result in tolerability issues. Hence, a broad spectrum anticonvulsant, with multiple mechanisms of action, that is well tolerated, would provide physicians with an important option in their armamentarium to control seizures. Felbamate initially fit this profile and was demonstrated to effectively control both partial and generalized seizures in clin. studies supporting registration. Unfortunately, unanticipated idiosyncratic toxicity was obsd. after approval and the drug is now relegated to second or third line therapy, depending on patient history and seizure type. Epileptologists still prescribe this drug for refractory seizures, and a recent communication indicates that 35,000 to 46,000 new patients have tried Felbatol (MedPointe Pharmaceuticals, Somerset, NJ) since 1995. The continued utilization of Felbatol, in light of its risk:benefit issues, highlights the need for new efficacious therapeutic options. Fluorofelbamate (Med-Pointe Pharmaceuticals), a phase I drug candidate, was designed to retain the broad spectrum multimechanistic activity of felbamate, with a modified metab. that has demonstrated, in vitro, to avoid the prodn. of the reactive metabolite believed to cause the idiosyncratic toxicity. This drug candidate is one of several carbamates either in development or currently on the market for treatment of seizures and other CNS disorders.
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  (b) Bialer, M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin. Invest. Drugs 2006, 15, 637– 647, DOI: 10.1517/13543784.15.6.637
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  Xu, S.; Zhu, B.; Teffera, Y.; Pan, D. E.; Caldwell, C. G.; Doss, G.; Stearns, R. A.; Evans, D. C.; Beconi, M. G. Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes. Drug Metab. Dispos. 2005, 33, 121– 130, DOI: 10.1124/dmd.104.001842
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  Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes
  Xu, Shiyao; Zhu, Bing; Teffera, Yohannes; Pan, Deborah E.; Caldwell, Charles G.; Doss, George; Stearns, Ralph A.; Evans, David C.; Beconi, Maria G.
  Drug Metabolism and Disposition (2005), 33 (1), 121-130CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)
  The current study evaluated the potential for two dipeptidyl peptidase-IV (DPP-IV) inhibitor analogs (1S)-1-(trans-4-{[(4-trifluoromethoxyphenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride and (1S)-1-(trans-4-{[(2,4-difluorophenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride (MRL-A and MRL-B), contg. a fluoropyrrolidine moiety in the structure, to undergo metabolic activation. The irreversible binding of these tritium-labeled compds. to rat liver microsomal protein was time- and NADPH-dependent and was attenuated by the addn. of reduced glutathione (GSH) or N-acetylcysteine (NAC) to the incubation, indicating that chem. reactive intermediates were formed and trapped by these nucleophiles. Mass spectrometric analyses and further trapping expts. with semicarbazide indicated that the fluoropyrrolidine ring had undergone sequential oxidn. and defluorination events resulting in the formation of GSH or NAC conjugates of the pyrrolidine moiety. The bioactivation of MRL-A was catalyzed primarily by rat recombinant CYP3A1 and CYP3A2. Pretreatment of rats with prototypic CYP3A1 and 3A2 inducers (pregnenolone-16α-carbonitrile and dexamethasone) enhanced the extent of bioactivation which, in turn, led to a higher degree of in vitro irreversible binding to microsomal proteins (5- and 9-fold increase, resp.). Herein, the authors describe studies that demonstrate that the fluoropyrrolidine ring is prone to metabolic activation and that GSH or NAC can trap the reactive intermediates to form adducts that provide insight into the mechanisms of bioactivation.
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51. 51
  (a) Edmondson, S. D.; Mastracchio, A.; Mathvink, R. J.; He, J.; Harper, B.; Park, Y. J.; Beconi, M.; Di Salvo, J.; Eiermann, G. J.; He, H.; Leiting, B.; Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.; Patel, S. B.; Petrov, A.; Scapin, G.; Shang, J.; Roy, R. S.; Smith, A.; Wu, J.K.; Xu, S.; Zhu, B.; Thornberry, N. A.; Weber, A. E. (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2006, 49, 3614– 3627, DOI: 10.1021/jm060015t
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  51a
  (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]- pyridin-6-ylphenyl)butanamide: A selective α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
  Edmondson, Scott D.; Mastracchio, Anthony; Mathvink, Robert J.; He, Jiafang; Harper, Bart; Park, You-Jung; Beconi, Maria; Di Salvo, Jerry; Eiermann, George J.; He, Huaibing; Leiting, Barbara; Leone, Joseph F.; Levorse, Dorothy A.; Lyons, Kathryn; Patel, Reshma A.; Patel, Sangita B.; Petrov, Aleksandr; Scapin, Giovanna; Shang, Jackie; Roy, Ranabir Sinha; Smith, Aaron; Wu, Joseph K.; Xu, Shiyao; Zhu, Bing; Thornberry, Nancy A.; Weber, Ann E.
  Journal of Medicinal Chemistry (2006), 49 (12), 3614-3627CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A series of β-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogs led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide I, a potent, orally active DPP-4 inhibitor (IC50 = 6.3 nM) with excellent selectivity, oral bioavailability in preclin. species, and in vivo efficacy in animal models. Compd. I was selected for further characterization as a potential new treatment for type 2 diabetes.
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  (b) Sharma, R.; Sun, H.; Piotrowski, D. W.; Ryder, T. F.; Doran, S. D.; Dai, H.; Prakash, C. Metabolism, excretion, and pharmacokinetics of (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone, a dipeptidyl peptidase inhibitor, in rat, dog and human. Drug Metab. Dispos. 2012, 40, 2143– 2161, DOI: 10.1124/dmd.112.047316
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  Tremblay, M.; Bethell, R. C.; Cordingley, M. G.; Deroy, P.; Duan, J.; Duplessis, M.; Edwards, P. J.; Faucher, A. M.; Halmos, T.; James, C. A.; Kuhn, C.; Lacoste, J. E.; Lamorte, L.; LaPlante, S. R.; Malenfant, É.; Minville, J.; Morency, L.; Morin, S.; Rajotte, D.; Salois, P.; Simoneau, B.; Tremblay, S.; Sturino, C. F. Identification of benzofurano-[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2775– 2780, DOI: 10.1016/j.bmcl.2013.02.042
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  (a) Meyer, A.; Imming, P. Benzylisoquinoline alkaloids from the papaveraceae: the heritage of Johannes Gadamer (1867–1928). J. Nat. Prod. 2011, 74, 2482– 2487, DOI: 10.1021/np2005049
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  (b) Sriram, D.; Yogeeswari, P.; Thirumurugan, R.; Ratan Bal, T. R. Camptothecin and its analogues: a review on their chemotherapeutic potential. Nat. Prod. Res. 2005, 19, 393– 412, DOI: 10.1080/14786410412331299005
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  Camptothecin and its analogues: a review on their chemotherapeutic potential
  Sriram, Dharmarajan; Yogeeswari, Perumal; Thirumurugan, Rathinasabapathy; Ratan Bal, Tanushree
  Natural Product Research (2005), 19 (4), 393-412CODEN: NPRAAT; ISSN:1478-6419. (Taylor & Francis Ltd.)
  A review. Topoisomerase I (Topo-I) is a major target for anticancer drug discovery and design. As a result, Topo-I inhibitors constitute an important class of the current anticancer drugs. To date, all of the Topo-I inhibitors that have been clin. evaluated are analogs of camptothecin (CPT), an ext. of the Chinese tree Camptotheca acuminata. CPT has shown significant antitumor activity to lung, ovarian, breast, pancreas and stomach cancers. In this article the, phytochem. aspect, and various structural modifications are comprehensively reviewed as in rings A, B, C, D and E. Biol. activity of camptothecin, other than anticancer, reported till the year 2003 has also been discussed.
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  (c) Olsen, L. R.; Grillo, M. P.; Skonberg, C. Constituents in kava extracts potentially involved in hepatotoxicity: a review. Chem. Res. Toxicol. 2011, 24, 992– 1002, DOI: 10.1021/tx100412m
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  Constituents in Kava Extracts Potentially Involved in Hepatotoxicity: A Review
  Olsen, Line R.; Grillo, Mark P.; Skonberg, Christian
  Chemical Research in Toxicology (2011), 24 (7), 992-1002CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
  A review. Aq. kava root prepns. have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava exts. in Western countries, where mainly ethanolic or acetonic exts. are used. The mechanism of toxicity has not been established, although several theories have been put forward. The compn. of the major constituents, the kava lactones, varies according to prepn. method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain compn. of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chem. structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones were identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addn. of GSH to kava exts. has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava ext., such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries.
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54. 54
  Murray, M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr. Drug Metab. 2000, 1, 67– 84, DOI: 10.2174/1389200003339270
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  Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation
  Murray, Michael
  Current Drug Metabolism (2000), 1 (1), 67-84CODEN: CDMUBU ISSN:. (Bentham Science Publishers Ltd.)
  A review with 110 refs. Cytochrome P 450 (CYP) enzymes catalyze the oxidative conversion of drugs and other lipophilic compds. to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidn. by specific CYPs, whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compds. have been widely employed as com. important pesticide synergists and a no. of derivs. are found in oils and spices. MDP compds. are of considerable toxicol. significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivs. produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clin. importance that possess the MDP structural feature, the synthesis and preclin. evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compds. it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chem. mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clin. value of new drugs.
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55. 55
  (a) Kalgutkar, A. S.; Gardner, I.; Obach, R. S.; Shaffer, C. L.; Callegari, E.; Henne, K. R.; Mutlib, A. E.; Dalvie, D. K.; Lee, J. S.; Nakai, Y.; O’Donnell, J. P.; Boer, J.; Harriman, S. P. A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 2005, 6, 161– 225, DOI: 10.2174/1389200054021799
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  A comprehensive listing of bioactivation pathways of organic functional groups
  Kalgutkar, Amit S.; Gardner, Iain; Obach, R. Scott; Shaffer, Christopher L.; Callegari, Ernesto; Henne, Kirk R.; Mutlib, Abdul E.; Dalvie, Deepak K.; Lee, Jae S.; Nakai, Yasuhiro; O'Donnell, John P.; Boer, Jason; Harriman, Shawn P.
  Current Drug Metabolism (2005), 6 (3), 161-225CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)
  A review. The occurrence of idiosyncratic adverse drug reactions during late clin. trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiol. of many drug-induced adverse reactions. Therefore, a thorough examn. of the biochem. reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochem. systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compds. based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as exptl. approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.
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  .
  (b) Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol. 2011, 24, 1345– 1410, DOI: 10.1021/tx200168d
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  55b
  Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States
  Stepan, Antonia F.; Walker, Daniel P.; Bauman, Jonathan; Price, David A.; Baillie, Thomas A.; Kalgutkar, Amit S.; Aleo, Michael D.
  Chemical Research in Toxicology (2011), 24 (9), 1345-1410CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
  A review. Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examd. as part of lead optimization efforts in drug discovery. Likewise, avoidance of "structural alerts" is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards assocd. with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addn., the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a mol. that contains a structural alert (RM pos. or neg.) a cause for concern. Could the mol. in its parent form exert toxicity. Can a low dose drug candidate truly mitigate metab.-dependent and -independent idiosyncratic toxicity risks. In an effort to address these questions, we have retrospectively examd. 68 drugs (recalled or assocd. with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochem. characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our anal. revealed that a significant proportion (∼78-86%) of drugs assocd. with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these mols. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochem. properties such as mol. wt., lipophilicity, etc. Approx. half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chem. architecture, and many were found to be RM-pos. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely assocd. with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addn., competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-pos. drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our anal. suggests a need for a more integrated screening paradigm for chem. hazard identification in drug discovery. Thus, in addn. to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compd.(s)) for lead compds., effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compd. liabilities. However, the prospective use of such data in compd. selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiol. mechanisms assocd. with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the assocd. "body burden" of the parent drug and its metabolites will remain an overarching goal in drug discovery.
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56. 56
  Bolton, J. L.; Trush, M. A.; Penning, T. M.; Dryhurst, G.; Monks, T. J. Role of quinones in toxicology. Chem. Res. Toxicol. 2000, 13, 135– 160, DOI: 10.1021/tx9902082
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  Role of Quinones in Toxicology
  Bolton, Judy L.; Trush, Michael A.; Penning, Trevor M.; Dryhurst, Glenn; Monks, Terrence J.
  Chemical Research in Toxicology (2000), 13 (3), 135-160CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
  A review and discussion with 298 refs. Quinones represent a class of toxicol. intermediates which can create a variety of hazardous effects in vivo, including acute cytotoxicity, immunotoxicity, and carcinogenesis. The mechanisms by which quinones cause these effects can be quite complex. Quinones are Michael acceptors, and cellular damage can occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active mols. which can redox cycle with their semiquinone radicals, leading to formation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Prodn. of ROS can cause severe oxidative stress within cells through the formation of oxidized cellular macromols., including lipids, proteins, and DNA. Formation of oxidatively damaged bases such as 8-oxodeoxyguanosine has been assocd. with aging and carcinogenesis. Furthermore, ROS can activate a no. of signaling pathways, including protein kinase C and RAS. This review explores the varied cytotoxic effects of quinones using specific examples, including quinones produced from benzene, polycyclic arom. hydrocarbons, estrogens, and catecholamines. The evidence strongly suggests that the numerous mechanisms of quinone toxicity (i.e., alkylation vs. oxidative stress) can be correlated with the known pathol. of the parent compd.(s).
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57. 57
  (a) Hemeryck, A.; De Vriendt, C. A.; Belpaire, F. M. Metoprolol-paroxetine interaction in human liver microsomes: stereoselective aspects and prediction of the in vivo interaction. Drug Metab. Dispos. 2001, 29, 656– 663
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  (b) Zhao, S. X.; Dalvie, D. K.; Kelly, J. M.; Soglia, J. R.; Frederick, K. S.; Smith, E. B.; Obach, R. S.; Kalgutkar, A. S. NADPH-dependent covalent binding of [³H]-paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 2007, 20, 1649– 1657, DOI: 10.1021/tx700132x
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  (c) Bertelsen, K. M.; Venkatakrishnan, K.; von Moltke, L. L.; Obach, R. S.; Greenblatt, D. J. Apparent mechanism-based inhibition of human CYP 2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 2003, 31, 289– 293, DOI: 10.1124/dmd.31.3.289
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  Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: Comparison with fluoxetine and quinidine
  Bertelsen, Kirk M.; Venkatakrishnan, Karthik; Von Moltke, Lisa L.; Obach, R. Scott; Greenblatt, David J.
  Drug Metabolism and Disposition (2003), 31 (3), 289-293CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)
  Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P 450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To det. whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estd. by varying the time of preincubation as well as the concn. of inhibitor. From these data, a Kitz-Wilson plot was constructed, allowing the estn. of both an apparent inactivator concn. required for half-maximal inactivation (KI) and the maximal rate const. of inactivation (KINACT) value for this interaction. Preincubation of paroxetine with human liver microsomes caused an approx. 8-fold redn. in the IC50 value (0.34 vs. 2.54 μM). Time-dependent inhibition was demonstrated with an apparent KI of 4.85 μM and an apparent KINACT value of 0.17 min-1. Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. This pattern is consistent with the metab. of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P 450 enzymes. In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine.
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58. 58
  (a) Anzali, S.; Mederski, W. W. K. R.; Osswald, M.; Dorsch, D. 1. Endothelin antagonists: search for surrogates of methylendioxyphenyl by means of a kohonen neural network. Bioorg. Med. Chem. Lett. 1998, 8, 11– 16, DOI: 10.1016/S0960-894X(97)10150-0
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  Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure-Activity Relationships and Discovery Strategies To Mitigate Drug-Drug Interaction Risks
  Orr, Suvi T. M.; Ripp, Sharon L.; Ballard, T. Eric; Henderson, Jaclyn L.; Scott, Dennis O.; Obach, R. Scott; Sun, Hao; Kalgutkar, Amit S.
  Journal of Medicinal Chemistry (2012), 55 (11), 4896-4933CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The importance of mitigating drug-drug interaction (DDI) risks, which arise from inhibition of major human cytochrome P 450 enzymes is a well-established component of the lead optimization process in drug discovery. More recently, there has been much interest in clin. DDIs potentially arising via time- and concn.-dependent cytochrome P 450 inhibition, a phenomenon consistent with mechanism-based inactivation. Inactivated P 450 is catalytically incompetent and must be replenished by newly synthesized protein. Consequently, time-dependent inhibition of P450s presents a greater safety concern compared to reversible inhibition because of the increased propensity for pharmacokinetic interactions upon multiple dosing and the sustained duration of these interactions after discontinuation of the mechanism-based inactivator. Mechanism-based or time-dependent P 450 inhibitors pose an addnl. risk of idiosyncratic drug toxicity since the mechanism of time-dependency often involves the formation of reactive metabolites, which can react with proteins other than the P 450 isoenzyme responsible for catalysis. in vitro time-dependent inhibition (TDI) of P 450 enzymes is now routinely assessed as part of lead optimization efforts in preclin. drug discovery. However, identification of an in vitro TDI liability can raise several questions such as: What is the mechanism of TDI. Does it involve the formation of reactive metabolites. Is there a 1:1 correlation between P 450 TDI and RM formation (as measured from reactive metabolite trapping studies). What is the likelihood that a P 450 time-dependent inhibitor will also cause toxicity. What are the DDI risk mitigation options when dealing with P 450 inactivators in drug discovery - compd. progression or termination. Several drugs exhibit in vitro TDI of P 450 enzymes, but only a fraction thereof causes clin. DDIs. Hence, when do we initiate labor-intensive medicinal chem. efforts to design compds. devoid of P 450 TDI liability. What are the best methods to precisely predict the likelihood of occurrence of clin. DDIs with drug candidates that inactivate P 450 enzymes. What are (if any) the qualifying considerations for clin. progression of a P 450 time-dependent inactivator with projected clin. DDI risks. In an effort to address these questions and hopefully provide answers to some of them, we embarked on the present venture wherein we highlight the current state-of-the-art knowledge in this field with a special emphasis on (a) available biochem. and mechanistic approaches in drug discovery to examine TDI of P 450 isoenzymes with new chem. entities, (b) structure-activity relationship studies with marketed drugs assocd. with DDIs via P 450 inactivation, (c) case studies of medicinal chem. tactics to abrogate P 450 inactivation liability, (d) strategies for progression of P 450 TDI-pos. drug candidates, and (e) the utility of in silico methodol., including the use of physiol.-based pharmacokinetic simulators, in drug discovery to predict the magnitude of clin. DDIs risks anticipated with new clin. candidates.
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  (e) Crawford, J. J.; Kenny, P. W.; Bowyer, J.; Cook, C. R.; Finlayson, J. E.; Heyes, C.; Highton, A. J.; Hudson, J. A.; Jestel, A.; Krapp, S.; Martin, S.; MacFaul, P. A.; McDermott, B. P.; McGuire, T. M.; Morley, A. D.; Morris, J. J.; Page, K. M.; Rosenbrier Ribeiro, L.; Sawney, H.; Steinbacher, S.; Smith, C.; Dossetter, A. G. Pharmacokinetic benefits of 3,4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors. J. Med. Chem. 2012, 55, 8827– 8837, DOI: 10.1021/jm301119s
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  Uttamsingh, V.; Gallegos, R.; Liu, J. F.; Harbeson, S. L.; Bridson, G. W.; Cheng, C.; Wells, D. S.; Graham, P. B.; Zelle, R.; Tung, R. Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine. J. Pharmacol. Exp. Ther. 2015, 354, 43– 54, DOI: 10.1124/jpet.115.223768
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  Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine
  Uttamsingh, Vinita; Gallegos, Richard; Liu, Julie F.; Harbeson, Scott L.; Bridson, Gary W.; Cheng, Changfu; Wells, David S.; Graham, Philip B.; Zelle, Robert; Tung, Roger
  Journal of Pharmacology and Experimental Therapeutics (2015), 354 (1), 43-54CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)
  Selective deuterium substitution as a means of ameliorating clin. relevant pharmacokinetic drug interactions is demonstrated in this study. Carbon-deuterium bonds are more stable than corresponding carbon-hydrogen bonds. Using a precision deuteration platform, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium. The new chem. entity, CTP-347 [(3S,4R)-3-((2,2-dideuterobenzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine], demonstrated similar selectivity for the serotonin receptor, as well as similar neurotransmitter uptake inhibition in an in vitro rat synaptosome model, as unmodified paroxetine. However, human liver microsomes cleared CTP-347 faster than paroxetine as a result of decreased inactivation of CYP2D6. In phase 1 studies, CTP-347 wasmetabolized more rapidly in humans and exhibited a lower pharmacokinetic accumulation index than paroxetine. These alterations in the metab. profile resulted in significantly reduced drug-drug interactions between CTP-347 and two other CYP2D6-metabolized drugs: tamoxifen (in vitro) and dextromethorphan (in humans). Our results show that precision deuteration can improve the metab. profiles of existing pharmacotherapies without affecting their intrinsic pharmacologies.
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60. 60
  (a) Vasudevan, A.; Wodka, D.; Verzal, M. K.; Souers, A. J.; Gao, J.; Brodjian, S.; Fry, D.; Dayton, B.; Marsh, K. C.; Hernandez, L. E.; Ogiela, C. A.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2. Bioorg. Med. Chem. Lett. 2004, 14, 4879– 4882, DOI: 10.1016/j.bmcl.2004.07.034
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  Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies
  Nuzzi, Andrea; Fiasella, Annalisa; Ortega, Jose Antonio; Pagliuca, Chiara; Ponzano, Stefano; Pizzirani, Daniela; Bertozzi, Sine Mandrup; Ottonello, Giuliana; Tarozzo, Glauco; Reggiani, Angelo; Bandiera, Tiziano; Bertozzi, Fabio; Piomelli, Daniele
  European Journal of Medicinal Chemistry (2016), 111 (), 138-159CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
  4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate I is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, the authors describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivs., which have led to the identification of I, and expand these studies to elucidate the principal structural and stereochem. features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of II, a novel inhibitor of human NAAA that shows an improved physicochem. and drug-like profile relative to I. This favorable profile, along with the structural diversity of the carbamic acid chain of I, identify this compd. as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.
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61. 61
  (a) Guo, Z.; Zhu, Y.-F.; Gross, T. D.; Tucci, F. C.; Gao, Y.; Moorjani, M.; Connors, P. .J., Jr.; Rowbottom, M. W.; Chen, Y.; Struthers, R. S.; Xie, Q.; Saunders, J.; Reinhart, G.; Chen, T. K.; Killam Bonneville, A. L.; Chen, C. Synthesis and Structure-activity relationships of 1-arylmethyl-5-aryl-6-methyluracils as potent gonadotropin-releasing hormone receptor antagonists. J. Med. Chem. 2004, 47, 1259– 1271, DOI: 10.1021/jm030472z
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  Malamas, M. S.; Erdei, J.; Gunawan, I.; Barnes, K.; Johnson, M.; Hui, Y.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Olland, A.; Bard, J.; Robichaud, A. J. Aminoimidazoles as potent and selective human β-secretase (BACE1) inhibitors. J. Med. Chem. 2009, 52, 6314– 6323, DOI: 10.1021/jm9006752
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  Rose, W. C.; Marathe, P. H.; Jang, G. R.; Monticello, T. M.; Balasubramanian, B. N.; Long, B.; Fairchild, C. R.; Wall, M. E.; Wani, M. C. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother. Pharmacol. 2006, 58, 73– 85, DOI: 10.1007/s00280-005-0128-y
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  Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization
  Rose, William C.; Marathe, Punit H.; Jang, Graham R.; Monticello, Thomas M.; Balasubramanian, Balu N.; Long, Byron; Fairchild, Craig R.; Wall, Monroe E.; Wani, Mansukh C.
  Cancer Chemotherapy and Pharmacology (2006), 58 (1), 73-85CODEN: CCPHDZ; ISSN:0344-5704. (Springer)
  Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacol., toxicol., metabolic and pharmacokinetic developmental potential. Methods: In vitro and in vivo assays were used to assess the compds. for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclin. antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicol. assessment of GI injury in mice. The generation of parent compd. from BMS-422461 was qual. similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equil. was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. Conclusions: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclin. GI toxicity, make this novel camptothecin analog attractive for clin. development.
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64. 64
  Trachsel, D.; Hadorn, M.; Baumberger, F. Synthesis of fluoro analogues of 3,4-(methylenedioxy)amphetamine (MDA) and its derivatives. Chem. Biodivers. 2009, 6, 2115– 2135
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65. 65
  (a) Van Goor, F.; Hadida, S.; Grootenhuis, P. D. J.; Burton, B.; Stack, J. H.; Straley, K. S.; Decker, C. J.; Miller, M.; McCartney, J.; Olson, E. R.; Wine, J. J.; Frizzell, R. A.; Ashlock, M.; Negulescu, P. A. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 18843– 18848, DOI: 10.1073/pnas.1105787108
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  65a
  Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
  Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A.
  Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (46), 18843-18848, S18843/1-S18843/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amts. of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small mols. Here we describe the in vitro pharmacol. of VX-809, a CFTR corrector that was advanced into clin. development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approx. 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level assocd. with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR cor. by VX-809 exhibited biochem. and functional characteristics similar to normal CFTR, including biochem. susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.
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  .
  (b) Deeks, E. D. Lumacaftor/ivacaftor: a review in cystic fibrosis. Drugs 2016, 76, 1191– 1201, DOI: 10.1007/s40265-016-0611-2
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  65b
  Lumacaftor/Ivacaftor: A Review in Cystic Fibrosis
  Deeks, Emma D.
  Drugs (2016), 76 (12), 1191-1201CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
  Lumacaftor/ivacaftor (Orkambi) is a fixed-dose tablet contg. a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride. In two 24-wk trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with std. therapy, was assocd. with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory vol. in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clin. meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI). In an ongoing extension of these studies (PROGRESS), lumacaftor plus ivacaftor provided clin. benefit over a further 72 wk of treatment. Lumacaftor plus ivacaftor had an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature. Thus, lumacaftor/ivacaftor expands the treatment options available for patients with cystic fibrosis homozygous for the F508del-CFTR mutation, although its precise place in clin. practice remains to be detd.
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66. 66
  Keith, J. M.; Jones, W. M.; Tichenor, M.; Liu, J.; Seierstad, M.; Palmer, J. A.; Webb, M.; Karbarz, M.; Scott, B. P.; Wilson, S. J.; Luo, L.; Wennerholm, M. L.; Chang, L.; Rizzolio, M.; Rynberg, R.; Chaplan, S. R.; Breitenbucher, J. G. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 2015, 6, 1204– 1208, DOI: 10.1021/acsmedchemlett.5b00353
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  66
  Preclinical Characterization of the FAAH Inhibitor JNJ-42165279
  Keith, John M.; Jones, William M.; Tichenor, Mark; Liu, Jing; Seierstad, Mark; Palmer, James A.; Webb, Michael; Karbarz, Mark; Scott, Brian P.; Wilson, Sandy J.; Luo, Lin; Wennerholm, Michelle L.; Chang, Leon; Rizzolio, Michele; Rynberg, Raymond; Chaplan, Sandra R.; Breitenbucher, J. Guy
  ACS Medicinal Chemistry Letters (2015), 6 (12), 1204-1208CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  The preclin. characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 I is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concns. of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compd. was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good phys., ADME, and PD properties of JNJ-42165279 supported it entering the clin. portfolio.
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67. 67
  Buissonneaud, D. Y.; van Mourik, T.; O’Hagan, D. A DFT study on the origin of the fluorine gauche effect in substituted fluoroethanes. Tetrahedron 2010, 66, 2196– 2202, DOI: 10.1016/j.tet.2010.01.049
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  67
  A DFT study on the origin of the fluorine gauche effect in substituted fluoroethanes
  Buissonneaud, David Y.; van Mourik, Tanja; O'Hagan, David
  Tetrahedron (2010), 66 (12), 2196-2202CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
  DFT derived conformational energy profiles of a series of β-substituted α-fluoroethanes (F-CH2CH2-X) have been explored where the substituent X was varied as NH3+, OCOH, NCO, NO2, NHCHO, F, N3, CH=NH, NCS, CH=C=CH2, CH3, CH=CH2, NC, CN, CHO, and CCH. Comparisons were correlated relative to 1,2-difluoroethane, a compd. which exhibits a well known gauche preference. Only four of the compds. displayed an anti preference, with the large majority preferring a gauche conformation. In particular the influence of steric and electrostatic attraction/repulsion between the fluorine atom and the X-substituent was explored by evaluating rotational energy profiles for all compds. and sep. NBO correlations were evaluated to assess the contribution of hyperconjugation to the minimized gauche and anti conformers. In the event the gauche preference for 1,2-difluoroethane was shown to have an origin due largely to σ(C-H)→σ*(C-F) hyperconjugative interactions, whereas the conformational preference for the remaining structures is rationalized by hyperconjugative as well as steric and electrostatic contributions. The anti preferred compds. 13, 14 and 16 possessed triple bonds and the preference arose due to fluorine/p-orbital repulsion.
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68. 68
  (a) Deniau, G.; Slawin, A. M. Z.; Lebl, T.; Chorki, F.; Issberner, J. P.; van Mourik, T.; Heygate, J. M.; Lambert, J. J.; Etherington, L. A.; Sillar, K. T.; O’Hagan, D. Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-γ-aminobutyric acid ((R)- and (S)-3F-GABA): an analogue of the neurotransmitter GABA. ChemBioChem 2007, 8, 2265– 2274, DOI: 10.1002/cbic.200700371
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  68a
  Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-γ-aminobutyric acid ((R)- and (S)-3F-GABA): an analog of the neurotransmitter GABA
  Deniau, Gildas; Slawin, Alexandra M. Z.; Lebl, Tomas; Chorki, Fatima; Issberner, Jon P.; van Mourik, Tanja; Heygate, Judith M.; Lambert, Jeremy J.; Etherington, Lori-An; Sillar, Keith T.; O'Hagan, David
  ChemBioChem (2007), 8 (18), 2265-2274CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
  β-Aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neurotransmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enantiomers of 3-fluoro-GABA (2, 3F-GABA). DFT calcns. were carried out in a continuum solvent model (PCM-B3LYP) to est. the preferred conformations of 3F-GABA in aq. soln. NMR coupling consts. were calcd. for each conformer and were then used to simulate the NMR spectra to evaluate the soln. conformation of 3F-GABA. A preliminary evaluation of the 3F-GABA enantiomers shows that they act similarly as agonists of cloned GABAA receptors; however, they behave quite differently in a whole animal (Xenopus laevis tadpole model).
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  .
  (b) Yamamoto, I.; Deniau, G. P.; Gavande, N.; Chebib, M.; Johnston, G. A. R.; O’Hagan, D. Agonist responses of (R)- and (S)-3-fluoro-γ-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABA_C receptors. Chem. Commun. 2011, 47, 7956– 7958, DOI: 10.1039/c1cc12141c
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  .
  (c) Clift, M. D.; Ji, H.; Deniau, G. P.; O’Hagan, D.; Silverman, R. B. Enantiomers of 4-amino-3-fluorobutanoic acid as substrates for γ-aminobutyric acid aminotransferase. Conformational probes for GABA binding. Biochemistry 2007, 46, 13819– 13828, DOI: 10.1021/bi701249q
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  68c
  Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for γ-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA Binding
  Clift, Michael D.; Ji, Haitao; Deniau, Gildas P.; O'Hagan, David; Silverman, Richard B.
  Biochemistry (2007), 46 (48), 13819-13828CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  γ-Aminobutyric acid aminotransferase (GABA-AT), a pyridoxal 5'-phosphate dependent enzyme, catalyzes the degrdn. of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) to succinic semialdehyde with concomitant conversion of pyridoxal 5'-phosphate (PLP) to pyridoxamine 5'-phosphate (PMP). The enzyme then catalyzes the conversion of α-ketoglutarate to the excitatory neurotransmitter L-glutamate. Racemic 4-amino-3-fluorobutanoic acid (3-F-GABA) was shown previously to act as a substrate for GABA-AT, not for transamination, but for HF elimination. Here we report studies of the reaction catalyzed by GABA-AT on (R)- and (S)-3-F-GABA. Neither enantiomer is a substrate for transamination. Very little elimination from the (S)-enantiomer was detected using a coupled enzyme assay; The rate of elimination of HF from the (R)-enantiomer is at least 10 times greater than that for the (S)-enantiomer. The (R)-enantiomer is about 20 times more efficient as a substrate for GABA-AT catalyzed HF elimination than GABA is a substrate for transamination. The (R)-enantiomer also inhibits the transamination of GABA 10 times more effectively than the (S)-enantiomer. Using a combination of computer modeling and the knowledge that vicinal C-F and C-NH3+ bonds have a strong preference to align gauche rather than anti to each other, it is concluded that on binding of free 3-F-GABA to GABA-AT the optimal conformation places the C-NH3+ and C-F bonds gauche in the (R)-enantiomer but anti in the (S)-enantiomer. Furthermore, the dynamic binding process and the bioactive conformation of GABA bound to GABA-AT have been inferred on the basis of the different biol. behavior of the two enantiomers of 3-F-GABA when they bind to the enzyme. The present study suggests that the C-F bond can be utilized as a conformational probe to explore the dynamic binding process and provide insight into the bioactive conformation of substrates, which cannot be easily detd. by other biophys. approaches.
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  .
  (d) Crittenden, D. L.; Chebib, M.; Jordan, M. J. T. A quantitative structure-activity relationship investigation into agonist binding at GABA_C receptors. J. Mol. Struct.: THEOCHEM 2005, 755, 81– 89, DOI: 10.1016/j.theochem.2005.07.029
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  68d
  A quantitative structure-activity relationship investigation into agonist binding at GABAC receptors
  Crittenden, Deborah L.; Chebib, Mary; Jordan, Meredith J. T.
  Journal of Molecular Structure: THEOCHEM (2005), 755 (1-3), 81-89CODEN: THEODJ; ISSN:0166-1280. (Elsevier B.V.)
  The quant. structure-activity relationship (QSAR) model constructed in this work represents the first quant. investigation into agonist binding at GABAC receptors. This model is based upon the three-dimensional structures of γ-aminobutyric acid (GABA) and 12 other biol. active GABA analogs. These structures are obtained by geometry optimization and conformational exploration at MP2/6-31 + G* within the conductor-like screening solvation model (COSMO). The biol. activity data are obtained from previous two-electrode voltage clamp electrophysiol. studies on recombinant GABAC ρ1 receptors expressed in Xenopus laevis oocytes. A QSAR model to predict GABAC agonist binding is constructed from mol. superposition data, generated by least-squares superposition of the stable aq. phase conformations of GABA and its known biol. active analogs to the bioactive conformation of TACA, the most potent GABAC receptor agonist. A significant relationship is found between the root-mean-squared deviation in at. position for the stable conformer of each GABA analog most closely fitting the template TACA structure and the natural log of the normalized biol. activity (R2 = 0.91, p < 0.0001), On the basis of mol. superposition and QSAR results, a pharmacophore model describing three-dimensional features and key interactions at the GABAC receptor binding site is proposed. As there exists no direct exptl. knowledge of structure of the GABAC binding site, this approach provides a feasible and reliable alternative to gain insight into its three-dimensional structure.
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69. 69
  (a) Hunter, L.; Jolliffe, K. A.; Jordan, M. J. T.; Jensen, P.; MacQuart, R. B. Synthesis and conformational analysis of α,β-difluoro-γ-amino acid derivatives. Chem. - Eur. J. 2011, 17, 2340– 2343, DOI: 10.1002/chem.201003320
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  69a
  Synthesis and conformational analysis of α,β-difluoro-γ-amino acid derivatives
  Hunter, Luke; Jolliffe, Katrina A.; Jordan, Meredith J. T.; Jensen, Paul; MacQuart, Rene B.
  Chemistry - A European Journal (2011), 17 (8), 2340-2343, S2340/1-S2340/61CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Synthetic access has been archived to all possible stereoisomers of the α,β-difluoro-γ-amino acid motif. These building blocks can readily be coupled to other amino acids under std. conditions with no detectable epimerization, and the resulting, diastereomeric peptides exhibit different, but predictable, conformational behavior. The α,β-difluoro-γ-amino acid motif described here should be of relevance in the future design of shape-controlled bioactive amino acids and peptides.
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  .
  (b) Yamamoto, I.; Jordan, M. J. T.; Gavande, N.; Doddareddy, M. R.; Chebib, M.; Hunter, L. The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABA C receptor. Chem. Commun. 2012, 48, 829– 831, DOI: 10.1039/C1CC15816C
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  69b
  The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABAC receptor
  Yamamoto, Izumi; Jordan, Meredith J. T.; Gavande, Navnath; Doddareddy, Munikumar R.; Chebib, Mary; Hunter, Luke
  Chemical Communications (Cambridge, United Kingdom) (2012), 48 (6), 829-831CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  The conformational behavior and GABA receptor activity of the different stereoisomers of 2,3-difluoro-4-aminobutyric acid are described. Two enantiomeric GABAC-active ligands are identified, one of which is an agonist while the other is an antagonist. The results support an existing QSAR model of the bioactive geometry of GABA at GABAC.
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70. 70
  Chia, P. W.; Livesey, M. R.; Slawin, A. M. Z.; Van Mourik, T.; Wyllie, D. J. A.; O’Hagan, D. 3-Fluoro-N-methyl-D-aspartic acid (3F-NMDA) stereoisomers as conformational probes for exploring agonist binding at NMDA receptors. Chem. - Eur. J. 2012, 18, 8813– 8819, DOI: 10.1002/chem.201200071
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  70
  3-Fluoro-N-methyl-L-aspartic acid (3F-NMDA) Stereoisomers as Conformational Probes for Exploring Agonist Binding at NMDA Receptors
  Chia, Poh Wai; Livesey, Matthew R.; Slawin, Alexandra M. Z.; Mourik, Tanja van; Wyllie, David J. A.; O'Hagan, David
  Chemistry - A European Journal (2012), 18 (28), 8813-8819, S8813/1-S8813/6CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  N-Methyl-L-aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a C-F bond at the 3-position of (S)-NMDA generates either the (2S,3S)- or (2S,3R)- diastereoisomers of 3F-NMDA. The individual diastereoisomers were prepd. by synthesis in enantiomerically pure forms and (2S,3S)-3F-NMDA is an agonist with a comparable potency to NMDA itself, whereas the (2S,3R)-diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the C-F bond (2S,3S)-3F-NMDA to adopt a gauche conformation to the C-N+ bond in the binding conformation, whereas the (2S,3R)-3F-NMDA forces these bonds anti, losing electrostatic stabilization, to achieve the required binding conformation. These observations illustrate the utility of stereoselective fluorination in influencing the mol. conformation of β-fluorinated amino acids and thus probing the active conformations of bioactive compds. at receptors.
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71. 71
  Hu, X. G.; Thomas, D. S.; Griffith, R.; Hunter, L. Stereoselective fluorination alters the geometry of a cyclic peptide: exploration of backbone-fluorinated analogues of unguisin A. Angew. Chem., Int. Ed. 2014, 53, 6176– 6179, DOI: 10.1002/anie.201403071
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  71
  Stereoselective fluorination alters the geometry of a cyclic peptide: Exploration of backbone-fluorinated analogues of Unguisin A
  Hu, Xiang-Guo; Thomas, Donald S.; Griffith, Renate; Hunter, Luke
  Angewandte Chemie, International Edition (2014), 53 (24), 6176-6179CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  New methods for enhancing the efficiency of peptide cyclization, and for fine-tuning the conformations of cyclic peptides, are valuable from a drug development perspective. Herein stereoselective fluorination is investigated as a new strategy for achieving these goals. Four vicinal difluorinated analogs of the natural cyclic heptapeptide unguisin A have been efficiently synthesized. The analogs are found to adopt dramatically different secondary structures, controlled by the fluorine stereochem.
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72. 72
  Hodges, J. A.; Raines, R. T. Stereoelectronic effects on collagen stability: the dichotomy of 4-fluoroproline diastereomers. J. Am. Chem. Soc. 2003, 125, 9262– 9263, DOI: 10.1021/ja035881z
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  72
  Stereoelectronic Effects on Collagen Stability: The Dichotomy of 4-Fluoroproline Diastereomers
  Hodges, Jonathan A.; Raines, Ronald T.
  Journal of the American Chemical Society (2003), 125 (31), 9262-9263CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Collagen is the most abundant protein in animals. Natural collagen consists of a triple helix of (Xaa-Yaa-Gly)n chains, in which the Xaa and Yaa residues are often L-proline. Here, a (2S,4S)-4-fluoroproline (flp) residue is shown to be greatly stabilizing in the Xaa position (but destabilizing in the Yaa position). In contrast, a (2S,4R)-4-fluoroproline (Flp) residue is shown to be greatly destabilizing in the Xaa position (but stabilizing in the Yaa position). The dichotomous effect of the diastereomers appears to arise from a gauche effect, which alters pyrrolidine ring pucker and hence properly (or improperly) preorganizes main-chain dihedral angles. Thus, the rational use of stereoelectronic effects can enhance the conformational stability of a protein.
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73. 73
  (a) Jakobsche, C. E.; Choudhary, A.; Miller, S. J.; Raines, R. T. n→π* Interaction and n)(π Pauli repulsion are antagonistic for protein stability. J. Am. Chem. Soc. 2010, 132, 6651– 6653, DOI: 10.1021/ja100931y
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  73a
  n → π* Interaction and n)(π Pauli Repulsion Are Antagonistic for Protein Stability
  Jakobsche, Charles E.; Choudhary, Amit; Miller, Scott J.; Raines, Ronald T.
  Journal of the American Chemical Society (2010), 132 (19), 6651-6653CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  In many common protein secondary structures, such as α-, 310, and polyproline II helixes, an n → π* interaction places the adjacent backbone amide carbonyl groups in close proximity to each other. This interaction, which is reminiscent of the Burgi-Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (Oi-1) of a peptide bond over the antibonding orbital (π*) of Ci:Oi of the subsequent peptide bond. Such a proximal arrangement of the amide carbonyl groups should be opposed by the Pauli repulsion between the lone pairs (n) of Oi-1 and the bonding orbital (π) of Ci:Oi. We explored the conformational effects of this Pauli repulsion by employing common peptidomimetics, wherein the n → π* interaction is attenuated while the Pauli repulsion is retained. Our results indicate that this Pauli repulsion prevents the attainment of such proximal arrangement of the carbonyl groups in the absence of the n → π* interaction. This finding indicates that the poor mimicry of the amide bond by many peptidomimetics stems from their inability to partake in the n → π* interaction and emphasizes the quantum-mech. nature of the interaction between adjacent amide carbonyl groups in proteins.
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  (b) Newberry, R. W.; VanVeller, B.; Guzei, I. A.; Raines, R. T. n→π* Interactions of amides and thioamides: implications for protein stability. J. Am. Chem. Soc. 2013, 135, 7843– 7846, DOI: 10.1021/ja4033583
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  73b
  n→π* Interactions of Amides and Thioamides: Implications for Protein Stability
  Newberry, Robert W.; VanVeller, Brett; Guzei, Ilia A.; Raines, Ronald T.
  Journal of the American Chemical Society (2013), 135 (21), 7843-7846CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Carbonyl-carbonyl interactions between adjacent backbone amides have been implicated in the conformational stability of proteins. By combining exptl. and computational approaches, we show that relevant amidic carbonyl groups assoc. through an n→π* donor-acceptor interaction with an energy of at least 0.27 kcal/mol. The n→π* interaction between two thioamides is 3-fold stronger than between two oxoamides due to increased overlap and reduced energy difference between the donor and acceptor orbitals. This result suggests that backbone thioamide incorporation could stabilize protein structures. Finally, we demonstrate that intimate carbonyl interactions are described more completely as donor-acceptor orbital interactions rather than dipole-dipole interactions.
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  (c) Kamer, K. J.; Choudhary, A.; Raines, R. T. Intimate interactions with carbonyl groups: dipole-dipole or n→π*?. J. Org. Chem. 2013, 78, 2099– 2103, DOI: 10.1021/jo302265k
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  73c
  Intimate Interactions with Carbonyl Groups: Dipole-Dipole or n→π*?
  Kamer, Kimberli J.; Choudhary, Amit; Raines, Ronald T.
  Journal of Organic Chemistry (2013), 78 (5), 2099-2103CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Amide carbonyl groups in proteins can engage in C-O···C=O and C-X···C=O interactions, where X is a halogen. The putative involvement of four poles suggests that these interactions are primarily dipolar. Our survey of crystal structures with a C-X···C=O contact that is short (i.e., within the sum of the X and C van der Waals radii) revealed no preferred C-X···C=O dihedral angle. Moreover, we found that structures with a short X-···C=O contact display the signatures of an n→π* interaction. We conclude that intimate interactions with carbonyl groups do not require a dipole.
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74. 74
  Fukushima, H.; Hiratate, A.; Takahashi, M.; Saito, M.; Munetomo, E.; Kitano, K.; Saito, H.; Takaoka, Y.; Yamamoto, K. Synthesis and structure–activity relationships of potent 3- or 4-substituted-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. 2004, 12, 6053– 6061, DOI: 10.1016/j.bmc.2004.09.010
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75. 75
  Jansen, K.; Heirbaut, L.; Verkerk, R.; Cheng, J. D.; Joossens, J.; Cos, P.; Maes, L.; Lambeir, A.-M.; De Meester, I.; Augustyns, K.; Van der Veken, P. Extended structure–activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP). J. Med. Chem. 2014, 57, 3053– 3074, DOI: 10.1021/jm500031w
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  75
  Extended Structure-Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP)
  Jansen, Koen; Heirbaut, Leen; Verkerk, Robert; Cheng, Jonathan D.; Joossens, Jurgen; Cos, Paul; Maes, Louis; Lambeir, Anne-Marie; De Meester, Ingrid; Augustyns, Koen; Van der Veken, Pieter
  Journal of Medicinal Chemistry (2014), 57 (7), 3053-3074CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncol. applications. The authors previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, the authors explore in detail the structure-activity relationship around this core scaffold. The authors report extensively optimized compds. that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compds. were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.
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76. 76
  Staas, D. D.; Savage, K. L.; Sherman, V. L.; Shimp, H. L.; Lyle, T. A.; Tran, L. O.; Wiscount, C. M.; McMasters, D. R.; Sanderson, P. E. J.; Williams, P. D.; Lucas, B. J., Jr.; Krueger, J. A.; Lewis, S. D.; White, R. B.; Yu, S.; Wong, B. K.; Kochansky, C. J.; Anari, M. R.; Yan, Y.; Vacca, J. P. Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability. Bioorg. Med. Chem. 2006, 14, 6900– 6916, DOI: 10.1016/j.bmc.2006.06.040
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  Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability
  Staas, Donnette D.; Savage, Kelly L.; Sherman, Vanessa L.; Shimp, Heidi L.; Lyle, Terry A.; Tran, Lekhanh O.; Wiscount, Catherine M.; McMasters, Daniel R.; Sanderson, Philip E. J.; Williams, Peter D.; Lucas, Bobby J.; Krueger, Julie A.; Lewis, S. Dale; White, Rebecca B.; Yu, Sean; Wong, Bradley K.; Kochansky, Christopher J.; Anari, M. Reza; Yan, Youwei; Vacca, Joseph P.
  Bioorganic & Medicinal Chemistry (2006), 14 (20), 6900-6916CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
  Previous reports from our labs. described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compds. for further optimization, we identified sites of metab. and designed analogs with 4-fluoroproline in P2 and cyclopropane-contg. side chains in P3 as an approach to reducing metab. and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs contg. (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compds. and by mol. modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compd. from this work, 41 (I), exhibits high potency in a coagulation assay in human plasma (2×APTT = 190 nM), excellent selectivity vs. the digestive enzyme trypsin (Ki = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg).
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77. 77
  Chiba, J.; Takayama, G.; Takashi, T.; Yokoyama, M.; Nakayama, A.; Baldwin, J. J.; McDonald, E.; Moriarty, K. J.; Sarko, C. R.; Saionz, K. W.; Swanson, R.; Hussain, Z.; Wong, A.; MachinagA, N. Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists. Bioorg. Med. Chem. 2006, 14, 2725– 2746, DOI: 10.1016/j.bmc.2005.11.058
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78. 78
  (a) Wang, Y.; Callejo, R.; Slawin, A. M. Z.; O’Hagan, D. The difluoromethylene (CF₂) group in aliphatic chains: synthesis and conformational preference of palmitic acids and nonadecane containing CF₂ groups. Beilstein J. Org. Chem. 2014, 10, 18– 25, DOI: 10.3762/bjoc.10.4
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  78a
  The difluoromethylene (CF2) group in aliphatic chains: synthesis and conformational preference of palmitic acids and nonadecane containing CF2 groups
  Wang, Yi; Callejo, Ricardo; Slawin, Alexandra M. Z.; O'Hagan, David
  Beilstein Journal of Organic Chemistry (2014), 10 (), 18-25, 8 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  The syntheses of palmitic acids and a nonadecane are reported with CF2 groups located 1,3 or 1,4 to each other along the aliph. chain. Specifically 8,8,10,10- and 8,8,11,11-tetrafluorohexadecanoic acids are prepd. as well as the singly modified analog 8,8-difluorohexadecanoic acid. Also 8,8,11,11-tetrafluorononadecane is prepd. as a pure hydrocarbon contg. a 1,4-di-CF2 motif. The modified palmitic acids are characterized by differential scanning calorimetry (DSC) to det. m.ps. and phase behavior relative to palmitic acid (62.5 °C). It emerges that 8,8,11,11-tetrafluorohexadecanoic acid, with the CF2 groups placed 1,4- to each other, has a significantly higher m.p. (89.9 °C) when compared to the other analogs and palmitic acid itself. It is a cryst. compd. and the structure reveals an extended anti-zig-zag chain. Similarly 8,8,11,11-tetrafluorononadecane adopts an extended anti-zig-zag structure. This is rationalized by dipolar relaxation between the two CF2 groups placed 1,4 to each other in the extended anti-zig-zag chain and suggests a design modification for long chain aliphatics which can introduce conformational stability.
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  (b) Tavasli, M.; O’Hagan, D.; Pearson, C.; Petty, M. C. The fluorine gauche effect. Langmuir isotherms report the relative conformational stability of (±)-erythro- and (±)-threo-9,10-difluorostearic acids. Chem. Commun. 2002, 1226– 1227, DOI: 10.1039/b202891c
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  78b
  The fluorine gauche effect. Langmuir isotherms report the relative conformational stability of (±)-erythro- and (±)-threo-9,10-difluorostearic acids
  Tavasli, Mustafa; O'Hagan, David; Pearson, Christopher; Petty, Michael C.
  Chemical Communications (Cambridge, United Kingdom) (2002), (11), 1226-1227CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  (±)-Erythro- and (±)-threo- 9,10-difluorostearic acids, which differ only by a stereogenic interconversion of a single C-F bond, have significantly different conformational stabilities.
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79. 79
  (a) O’Hagan, D. Organofluorine chemistry: synthesis and conformation of vicinal fluoromethylene motifs. J. Org. Chem. 2012, 77, 3689– 3699, DOI: 10.1021/jo300044q
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  79a
  Organofluorine Chemistry: Synthesis and Conformation of Vicinal Fluoromethylene Motifs
  O'Hagan, David
  Journal of Organic Chemistry (2012), 77 (8), 3689-3699CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A review. The C-F bond is the most polar bond in org. chem., and thus the bond has a relatively large dipole moment with a significant -ve charge d. on the fluorine atom and correspondingly a +ve charge d. on carbon. The electrostatic nature of the bond renders it the strongest one in org. chem. However, the fluorine atom itself is nonpolarizable, and thus, despite the charge localization on fluorine, it is a poor hydrogen-bonding acceptor. These properties of the C-F bond make it attractive in the design of nonviscous but polar org. compds., with a polarity limited to influencing the intramol. nature of the mol. and less so intermol. interactions with the immediate environment. In this perspective, the synthesis of aliph. chains carrying multivicinal fluoromethylene motifs is described. It emerges that the dipoles of adjacent C-F bonds orientate relative to each other, and thus, individual diastereoisomers display different backbone carbon chain conformations. These conformational preferences recognize the influence of the well-known gauche effect assocd. with 1,2-difluoroethane but extend to considering 1,3-fluorine-fluorine dipolar repulsions. The synthesis of carbon chains carrying two, three, four, five, and six vicinal fluoromethylene motifs is described, with an emphasis on the research done by the authors. These motifs obey almost predictable conformational behavior, and they emerge as candidates for inclusion in the design of performance org. mols.
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  (b) Wu, D.; Tian, A.; Sun, H. Conformational properties of 1,3-difluoropropane. J. Phys. Chem. A 1998, 102, 9901– 9905, DOI: 10.1021/jp982164w
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  79b
  Conformational properties of 1,3-difluoropropane
  Wu, D.; Tian, A.; Sun, H.
  Journal of Physical Chemistry A (1998), 102 (48), 9901-9905CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
  The conformational energy order of F(CH2)3F (I) is identified as GG < AG < AA < GG' at various ab initio calcn. levels. This result is analyzed on the basis of the mol. structures, partial charge distributions, and a mol.-mechanics calcn. A strong dipole-dipole interaction between the highly polarized C-F bonds is the decisive factor detg. the conformational-energy preference between 2 gauche-gauche conformers (GG and GG'). This observation suggests that, in addn. to the gauche effect, the intramol. electrostatic interaction should be considered for studying conformational behaviors of mols. with highly polarized bonds in general. The conformational energies obtained in this work challenge earlier interpretations of exptl. data for I.
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  (c) Hunter, L.; Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and structure of stereoisomeric multivicinal hexafluoroalkanes. Angew. Chem., Int. Ed. 2009, 48, 5457– 5460, DOI: 10.1002/anie.200901956
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  Synthesis and Structure of Stereoisomeric Multivicinal Hexafluoroalkanes
  Hunter, Luke; Kirsch, Peer; Slawin, Alexandra M. Z.; O'Hagan, David
  Angewandte Chemie, International Edition (2009), 48 (30), 5457-5460, S5457/1-S5457/63CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The syntheses of hexafluoroalkanes 1a (I) and 1b (II), and tetrafluoroalkane 2 (III) are described. The conformational behavior of 1a (helix), 1b (zigzag), and 2 (zigzag) is consistent with two stereochem. preferences: parallel 1,3-C-F bonds are avoided, and gauche 1,2-C-F bonds are favored.
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80. 80
  Scheidt, F.; Selter, P.; Santschi, N.; Holland, M. C.; Dudenko, D. V.; Daniliuc, C.; Mück-Lichtenfeld, C.; Hansen, M. R.; Gilmour, R. Emulating natural product conformation by cooperative, non-covalent fluorine interactions. Chem. - Eur. J. 2017, 23, 6142– 6149, DOI: 10.1002/chem.201604632
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  Emulating Natural Product Conformation by Cooperative, Non-Covalent Fluorine Interactions
  Scheidt, Felix; Selter, Philipp; Santschi, Nico; Holland, Mareike C.; Dudenko, Dmytro V.; Daniliuc, Constantin; Mueck-Lichtenfeld, Christian; Hansen, Michael Ryan; Gilmour, Ryan
  Chemistry - A European Journal (2017), 23 (25), 6142-6149CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Pervasive in Nature, the propane unit is an essential component of numerous bioactive mols. These range from acyclic systems, such as the neurotransmitter γ-aminobutyric acid, through to the bicyclic nuclei of various chromanes and dihydrobenzofurans. In the latter case, cyclization via cyclic ether formation ensures a highly pre-organized structure, while linear scaffolds display more dynamic conformational behavior resulting from rotation about the two internal C(sp3)-C(sp3) bonds. In this study, the replacement of -[CH2]- units by -[CHF]- centers is evaluated as a strategy to achieve acyclic conformational control by hindering these internal rotations. Reinforcing, non-covalent fluorine interactions are validated as powerful design features that result in programmable conformational behaviors: These are encoded by the relative configuration of each center. By exploiting cooperative neighboring stereoelectronic effects in a multi-vicinal fluoroalkane it is possible to emulate the overall conformation of the dihydrobenzofuran scaffold found in a variety of natural products with an acyclic mimic. This is described as a function of two bond vectors at the chain termini and validated by combined theor., crystallog. and spectroscopic analyses. In view of the favorable physicochem. properties assocd. with fluorine introduction, this approach to bioactive scaffold design may prove to be expansive.
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81. 81
  Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041– 9060, DOI: 10.1021/acs.jmedchem.5b01455
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  81
  Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery
  Huchet, Quentin A.; Kuhn, Bernd; Wagner, Bjorn; Kratochwil, Nicole A.; Fischer, Holger; Kansy, Manfred; Zimmerli, Daniel; Carreira, Erick M.; Muller, Klaus
  Journal of Medicinal Chemistry (2015), 58 (22), 9041-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The synthesis of a collection of 3-substituted indole derivs. incorporating partially fluorinated Pr and Bu groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aq. soly., and metabolic stability. The exptl. observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit mol. design in medicinal chem. and, more broadly, in life as well as materials sciences.
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82. 82
  Yokokawa, F.; Wang, G.; Chan, W. L.; Ang, S. H.; Wong, J.; Ma, I.; Rao, S. P. S.; Manjunatha, U.; Lakshminarayana, S. B.; Herve, M.; Kounde, C.; Tan, B. H.; Thayalan, P.; Ng, S. H.; Nanjundappa, M.; Ravindran, S.; Gee, P.; Tan, M.; Wei, L.; Goh, A.; Chen, P.-Y.; Lee, K. S.; Zhong, C.; Wagner, T.; Dix, I.; Chatterjee, A. K.; Pethe, K.; Kuhen, K.; Glynne, R.; Smith, P.; Bifani, P.; Jiricek, J. Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents. ACS Med. Chem. Lett. 2013, 4, 451– 455, DOI: 10.1021/ml400071a
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  Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents
  Yokokawa, Fumiaki; Wang, Gang; Chan, Wai Ling; Ang, Shi Hua; Wong, Josephine; Ma, Ida; Rao, Srinivasa P. S.; Manjunatha, Ujjini; Lakshminarayana, Suresh B.; Herve, Maxime; Kounde, Cyrille; Tan, Bee Huat; Thayalan, Pamela; Dick, Thomas; Ng, Seow Hwee; Nanjundappa, Mahesh; Ravindran, Sindhu; Gee, Peck; Tan, Maria; Wei, Liu; Goh, Anne; Chen, Pei-Yu; Lee, Kok Sin; Zhong, Chen; Wagner, Trixie; Dix, Ina; Chatterjee, Arnab K.; Pethe, Kevin; Kuhen, Kelli; Glynne, Richard; Smith, Paul; Bifani, Pablo; Jiricek, Jan
  ACS Medicinal Chemistry Letters (2013), 4 (5), 451-455CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  Nonracemic (aryl)(fluoroalkyl)tetrahydropyrazolo[1,5-a]pyrimidinecarboxamides I [R = 4-MeC6H4, 5-Me-2-pyridinyl, 5-methyl-2-furyl, 4-(4-morpholinyl)C6H4, 4-(MeOCH2CH2O)C6H4, 4-(3-oxetanyloxy)C6H4; R1 = F3C, F2HC; R2 = 4-FC6H4CH2, 6-MeO-3-pyridinylmethyl, 5-F-2-pyridinylmethyl] were prepd. stereoselectively as potential antitubercular agents; their inhibition of Mycobacterium tuberculosis (Mtb), their aq. solubilities, their plasma protein binding, and their lipophilicities were detd. I were prepd. from aryl Me ketones, Et trifluoro- or difluoroacetate, and Et 3-amino-4-pyrazolecarboxylate; resoln. of the intermediate cis-aryl(fluoroalkyl)tetrahydropyrazolopyrimidinecarboxylic acids by supercrit. fluid chromatog. followed by amidation or aryl modifications yielded the desired products. While I inhibited Mtb with MIC of 0.13-52.2 μM, ent-I did not inhibit Mtb (MIC > 20 μM). In particular, I (R = 4-MeC6H4; R1 = F3C; R2 = 4-FC6H4CH2) showed a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse antitubercular efficacy model, achieving a redn. of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. I (R = 4-MeC6H4; R1 = F3C; R2 = 4-FC6H4CH2) is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB. The structure of a nonracemic (methylpyridinyl)(trifluoromethyl)tetrahydropyrazolopyrimidinecarboxylic acid intermediate and its abs. configuration were detd. by X-ray crystallog.
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83. 83
  Koerts, J.; Soffers, A. E. M. F.; Vervoort, J.; De Jager, A.; Rietjens, I. M. C. M. Occurrence of the NIH shift upon the cytochrome P450-catalyzed in vivo and in vitro aromatic ring hydroxylation of fluorobenzenes. Chem. Res. Toxicol. 1998, 11, 503– 512, DOI: 10.1021/tx980053i
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  83
  Occurrence of the NIH Shift upon the Cytochrome P450-Catalyzed in Vivo and in Vitro Aromatic Ring Hydroxylation of Fluorobenzenes
  Koerts, Janneke; Soffers, Ans E. M. F.; Vervoort, Jacques; De Jager, Adrie; Rietjens, Ivonne M. C. M.
  Chemical Research in Toxicology (1998), 11 (5), 503-512CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
  The in vivo cytochrome P 450-catalyzed arom. hydroxylation of a series of fluorobenzenes was investigated with special emphasis on the importance of the fluorine NIH shift. The results obtained demonstrate a minor role for the NIH shift in the metab. of the fluorobenzenes to phenolic metabolites in control male Wistar rats. These in vivo results could indicate that (1) the NIH shift is an inherently minor process for fluorine substituents or (2) it is a potentially significant process but the presumed epoxide that leads to formation of the NIH-shifted metabolite is lost to an alternative metabolic pathway. In contrast to the in vivo data, in vitro expts. showed a significant amt. of NIH-shifted metabolites for 1,4-difluorobenzene. This result eliminates the explanation that the NIH shift is an inherently minor process for fluorine substituents. Results of addnl. expts. presented in this paper show that the reduced tendency of fluorine-substituted benzenes to undergo an NIH shift in vivo can-at least in part-be ascribed to the possible existence of alternative pathways for metab. of the epoxide, such as, for example, GSH conjugation, being more efficient for fluorinated than chlorinated benzenes.
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84. 84
  (a) Shih, I.-h.; Vliegen, I.; Peng, B.; Yang, H.; Hebner, C.; Paeshuyse, J.; Purstinger, G.; Fenaux, M.; Tian, Y.; Mabery, E.; Qi, X.; Bahador, G.; Paulson, M.; Lehman, L. S.; Bondy, S.; Tse, W.; Reiser, H.; Lee, W. A.; Schmitz, U.; Neyts, J.; Zhong, W. Mechanistic characterization of GS-9190 (tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase. Antimicrob. Agents Chemother. 2011, 55, 4196– 4203, DOI: 10.1128/AAC.00307-11
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  .
  (b) Hebner, C. M.; Han, B.; Brendza, K. M.; Nash, M.; Sulfab, M.; Tian, Y.; Hung, M.; Fung, W.; Vivian, R. W.; Trenkle, J.; Taylor, J.; Bjornson, K.; Bondy, S.; Liu, X.; Link, J.; Neyts, J.; Sakowicz, R.; Zhong, W.; Tang, H.; Schmitz, U. The HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function. PLoS One 2012, 7, e39163, DOI: 10.1371/journal.pone.0039163
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  84b
  The HCV non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function
  Hebner, Christy M.; Han, Bin; Brendza, Katherine M.; Nash, Michelle; Sulfab, Maisoun; Tian, Yang; Hung, Magdeleine; Fung, Wanchi; Vivian, Randall W.; Trenkle, James; Taylor, James; Bjornson, Kyla; Bondy, Steven; Liu, Xiaohong; Link, John; Neyts, Johan; Sakowicz, Roman; Zhong, Weidong; Tang, Hengli; Schmitz, Uli
  PLoS One (2012), 7 (6), e39163CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  Tegobuvir (TGV) is a novel non-nucleoside inhibitor (NNI) of HCV RNA replication with demonstrated antiviral activity in patients with genotype 1 chronic HCV infection. The mechanism of action of TGV has not been clearly defined despite the identification of resistance mutations mapping to the NS5B polymerase region. TGV does not inhibit NS5B enzymic activity in biochem. assays in vitro, suggesting a more complex antiviral mechanism with cellular components. Here, we demonstrate that TGV exerts anti-HCV activity utilizing a unique chem. activation and subsequent direct interaction with the NS5B protein. Treatment of HCV subgenomic replicon cells with TGV results in a modified form of NS5B with a distinctly altered mobility on a SDS-PAGE gel. Further anal. reveals that the aberrantly migrating NS5B species contains the inhibitor mol. Formation of this complex does not require the presence of any other HCV proteins. The intensity of the aberrantly migrating NS5B species is strongly dependent on cellular glutathione levels as well as CYP 1A activity. Furthermore anal. of NS5B protein purified from a heterologous expression system treated with TGV by mass spectrometry suggests that TGV undergoes a CYP-mediated intracellular activation step and the resulting metabolite, after forming a glutathione conjugate, directly and specifically interacts with NS5B. Taken together, these data demonstrate that upon metabolic activation TGV is a specific, covalent inhibitor of the HCV NS5B polymerase and is mechanistically distinct from other classes of the non-nucleoside inhibitors (NNI) of the viral polymerase.
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  .
  (c) Leivers, M.; Miller, J. F.; Chan, S. A.; Lauchli, R.; Liehr, S.; Mo, W.; Ton, T.; Turner, E. M.; Youngman, M.; Falls, J. G.; Long, S.; Mathis, A.; Walker, J. Imidazopyridazine hepatitis C virus polymerase inhibitors. Structure-activity relationship studies and the discovery of a novel, traceless prodrug mechanism. J. Med. Chem. 2014, 57, 1964– 1975, DOI: 10.1021/jm401337x
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  (d) Powers, J. P.; Piper, D. E.; Li, Y.; Mayorga, V.; Anzola, J.; Chen, J. M.; Jaen, J. C.; Lee, G.; Liu, J.; Peterson, M. G.; Tonn, G. R.; Ye, Q.; Walker, N. P. C.; Wang, Z. SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase. J. Med. Chem. 2006, 49, 1034– 1046, DOI: 10.1021/jm050859x
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  84d
  SAR and Mode of Action of Novel Non-Nucleoside Inhibitors of Hepatitis C NS5b RNA Polymerase
  Powers, Jay P.; Piper, Derek E.; Li, Yang; Mayorga, Veronica; Anzola, John; Chen, James M.; Jaen, Juan C.; Lee, Gary; Liu, Jinqian; Peterson, M. Greg; Tonn, George R.; Ye, Qiuping; Walker, Nigel P. C.; Wang, Zhulun
  Journal of Medicinal Chemistry (2006), 49 (3), 1034-1046CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochem. potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were detd. by x-ray crystallog., and the inhibitors were found to bind in an allosteric binding site sep. from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compds. in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
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85. 85
  Pinto, D. J.P.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.; Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. Discovery of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem. 2001, 44, 566– 578, DOI: 10.1021/jm000409z
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86. 86
  Alex, A.; Millan, D. S.; Perez, M.; Wakenhut, F.; Whitlock, G. A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. MedChemComm 2011, 2, 669– 674, DOI: 10.1039/c1md00093d
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  86
  Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space
  Alex, Alexander; Millan, David S.; Perez, Manuel; Wakenhut, Florian; Whitlock, Gavin A.
  MedChemComm (2011), 2 (7), 669-674CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  Utilizing 'beyond rule of five' chem. space is becoming increasingly important in drug design, but is usually at odds with good oral absorption. The formation of intramol. hydrogen bonds in drug mols. is hypothesised to shield polarity facilitating improved membrane permeability and intestinal absorption. NMR based evidence for intramol. hydrogen bonding in several 'beyond rule of five' oral drugs is described. Furthermore, the propensity for these drugs to form intramol. hydrogen bonds could be predicted for through modeling the lowest energy conformation in the gas phase. The modulation of apparent lipophilicity through intramol. hydrogen bonding in these mols. is supported by intrinsic cell permeability and intestinal absorption data in rat and human.
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87. 87
  (a) Hitchcock, S. A. Structural modifications that alter the P-glycoprotein efflux properties of compounds. J. Med. Chem. 2012, 55, 4877– 4895, DOI: 10.1021/jm201136z
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  87a
  Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds
  Hitchcock, Stephen A.
  Journal of Medicinal Chemistry (2012), 55 (11), 4877-4895CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  This perspective is focused on structural modifications and strategies that can be applied during compd. optimization in order to modulate the P-glycoprotein efflux properties of small mols. with a particular emphasis on implications for CNS penetration. The precise mol. interactions that confer P-glycoprotein efflux remain relatively poorly defined. The promiscuous nature of P-glycoprotein efflux renders the rational circumvention of efflux, while simultaneously optimizing compds. for eficacy, safety, and pharmacokinetic properties, an extremely challenging undertaking.
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  .
  (b) Desai, P. V.; Raub, T. J.; Blanco, M. J. How hydrogen bonds impact P-glycoprotein transport and permeability. Bioorg. Med. Chem. Lett. 2012, 22, 6540– 6548, DOI: 10.1016/j.bmcl.2012.08.059
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  87b
  How hydrogen bonds impact P-glycoprotein transport and permeability
  Desai, Prashant V.; Raub, Thomas J.; Blanco, Maria-Jesus
  Bioorganic & Medicinal Chemistry Letters (2012), 22 (21), 6540-6548CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  A review. The requirement to cross a biol. membrane can be a complex process esp. if multidrug transporters such as P-gp must be considered. Drug partitioning into the lipid membrane and efflux by P-gp are tightly coupled processes wherein H-bonding interactions play a key role. All H-bond donors and acceptors are not equal in terms of the strength of the H-bonds that they form, hence it is important to consider their relative strength. Using various examples from literature, we illustrate the benefits of considering the relative strengths of individual H-bonds and introducing intramol. H-bonds to increase membrane permeability and/or decrease P-gp efflux.
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88. 88
  (a) Dalvit, C.; Vulpetti, A. Intermolecular and intramolecular hydrogen bonds involving fluorine atoms: implications for recognition, selectivity, and chemical properties. ChemMedChem 2012, 7, 262– 272, DOI: 10.1002/cmdc.201100483
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  88a
  Intermolecular and Intramolecular Hydrogen Bonds Involving Fluorine Atoms: Implications for Recognition, Selectivity, and Chemical Properties
  Dalvit, Claudio; Vulpetti, Anna
  ChemMedChem (2012), 7 (2), 262-272CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A correlation between 19F NMR isotropic chem. shift and close intermol. F···H-X contacts (with X = N or O) has been identified upon anal. of the X-ray crystal structures of fluorinated mols. listed in the Cambridge Structural Database (CSD). An optimal F···X distance involving primary and shielded secondary fluorine atoms in hydrogen-bond formation along with a correlation between F···H distance and F···H-X angle were also derived from the anal. The hydrogen bonds involving fluorine are relevant, not only for the recognition mechanism and stabilization of a preferred conformation, but also for improvement in the permeability of the mols., as shown with examples taken from a proprietary database. Results of an anal. of the small no. of fluorine-contg. natural products listed in the Protein Data Bank (PDB) appear to strengthen the derived correlation between 19F NMR isotropic chem. shift and interactions involving fluorine (also known as the "rule of shielding") and provides a hypothesis for the recognition mechanism and catalytic activity of specific enzymes. Novel chem. scaffolds, based on the rule of shielding, have been designed for recognizing distinct structural motifs present in proteins. It is envisaged that this approach could find useful applications in drug design for the efficient optimization of chem. fragments or promising compds. by increasing potency and selectivity against the desired biomol. target.
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  (b) Dalvit, C.; Invernizzi, C.; Vulpetti, A. Fluorine as a hydrogen-bond acceptor: experimental evidence and computational calculations. Chem. - Eur. J. 2014, 20, 11058– 11068, DOI: 10.1002/chem.201402858
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  88b
  Fluorine as a Hydrogen-Bond Acceptor: Experimental Evidence and Computational Calculations
  Dalvit, Claudio; Invernizzi, Christian; Vulpetti, Anna
  Chemistry - A European Journal (2014), 20 (35), 11058-11068CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Hydrogen-bonding interactions play an important role in many chem. and biol. systems. Fluorine acting as a hydrogen-bond acceptor in intermol. and intramol. interactions was the subject of many controversial discussions and there are different opinions about it. Recently, the authors proposed a correlation between the propensity of fluorine to be involved in hydrogen bonds and its 19F NMR chem. shift. The authors now provide addnl. exptl. and computational evidence for this correlation. The strength of hydrogen-bond complexes involving the fluorine moieties CH2F, CHF2, and CF3 was measured and characterized in simple systems by using established and novel NMR methods and compared to the known hydrogen-bond complex formed between acetophenone and p-fluorophenol. Implications of these results for 19F NMR screening are analyzed. Computed values of the mol. electrostatic potential at the different fluorine atoms and the anal. of the electron d. topol. at bond crit. points correlate well with the NMR results.
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89. 89
  Weiss, M. M.; Williamson, T.; Babu-Khan, S.; Bartberger, M. D.; Brown, J.; Chen, K.; Cheng, Y.; Citron, M.; Croghan, M. D.; Dineen, T. A.; Esmay, J.; Graceffa, R. F.; Harried, S. S.; Hickman, D.; Hitchcock, S. A.; Horne, D. B.; Huang, H.; Imbeah-Ampiah, R.; Judd, T.; Kaller, M. R.; Kreiman, C. R.; La, D. S.; Li, V.; Lopez, P.; Louie, S.; Monenschein, H.; Nguyen, T. T.; Pennington, L. D.; Rattan, C.; San Miguel, T.; Sickmier, E. A.; Wahl, R. C.; Wen, P. H.; Wood, S.; Xue, Q.; Yang, B. H.; Patel, V. F.; Zhong, W. Design and preparation of a potent series of hydroxyethylamine containing β-secretase inhibitors that demonstrate robust reduction of central β-amyloid. J. Med. Chem. 2012, 55, 9009– 9024, DOI: 10.1021/jm300119p
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90. 90
  Swahn, B.-M.; Kolmodin, K.; Karlström, S.; von Berg, S.; Söderman, P.; Holenz, J.; Berg, S.; Lindström, J.; Sundström, M.; Turek, D.; Kihlström, J.; Slivo, C.; Andersson, L.; Pyring, D.; Rotticci, D.; Öhberg, L.; Kers, A.; Bogar, K.; von Kieseritzky, F.; Bergh, M.; Olsson, L.-L.; Janson, J.; Eketjäll, S.; Georgievska, B.; Jeppsson, F.; Fälting, J. Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides. J. Med. Chem. 2012, 55, 9346– 9361, DOI: 10.1021/jm3009025
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  90
  Design and Synthesis of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of β-Amyloid Peptides
  Swahn, Britt-Marie; Kolmodin, Karin; Karlstroem, Sofia; von Berg, Stefan; Soederman, Peter; Holenz, Joerg; Berg, Stefan; Lindstroem, Johan; Sundstroem, Marie; Turek, Dominika; Kihlstroem, Jacob; Slivo, Can; Andersson, Lars; Pyring, David; Rotticci, Didier; Oehberg, Liselotte; Kers, Annika; Bogar, Krisztian; Bergh, Margareta; Olsson, Lise-Lotte; Janson, Juliette; Eketjaell, Susanna; Georgievska, Biljana; Jeppsson, Fredrik; Faelting, Johanna
  Journal of Medicinal Chemistry (2012), 55 (21), 9346-9361CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clin. candidate drug for Alzheimer's disease, (S)-32 (I, AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain redn. of Aβ40, is discussed. Due to the basic nature of these compds., they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 (II) and (R)-41 (III) showing large in vitro margins with BACE1 cell IC50 values of 8.6 and 0.16 nM, resp., and hERG IC50 values of 16 and 2.8 μM, resp. Several compds. were advanced into pharmacodynamic studies and demonstrated significant redn. of β-amyloid peptides in mouse brain following oral dosing.
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91. 91
  Bell, I. M.; Bednar, R. A.; Fay, J. F.; Gallicchio, S. N.; Hochman, J. H.; McMasters, D. R.; Miller-Stein, C.; Moore, E. L.; Mosser, S. D.; Pudvah, N. T.; Quigley, A. G.; Salvatore, C. A.; Stump, C. A.; Theberge, C. R.; Wong, B. K.; Zartman, C. B.; Zhang, X. F.; Kane, S. A.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 6165– 6169, DOI: 10.1016/j.bmcl.2006.09.045
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  91
  Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists
  Bell, Ian M.; Bednar, Rodney A.; Fay, John F.; Gallicchio, Steven N.; Hochman, Jerome H.; McMasters, Daniel R.; Miller-Stein, Cynthia; Moore, Eric L.; Mosser, Scott D.; Pudvah, Nicole T.; Quigley, Amy G.; Salvatore, Christopher A.; Stump, Craig A.; Theberge, Cory R.; Wong, Bradley K.; Zartman, C. Blair; Zhang, Xu-Fang; Kane, Stefanie A.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.
  Bioorganic & Medicinal Chemistry Letters (2006), 16 (24), 6165-6169CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
  A rapid analog approach to identification of spirohydantoin-based CGRP antagonists provided novel, low mol. wt. leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compd. 12 (I), a potent CGRP receptor antagonist (Ki = 21 nM) with good oral bioavailability in three species.
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92. 92
  Koshizawa, T.; Morimoto, T.; Watanabe, G.; Watanabe, T.; Yamasaki, N.; Sawada, Y.; Fukuda, T.; Okuda, A.; Shibuya, K.; Ohgiya, T. Optimization of a novel series of potent and orally bioavailable GPR119 agonists. Bioorg. Med. Chem. Lett. 2017, 27, 3249– 3253, DOI: 10.1016/j.bmcl.2017.06.034
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  92
  Optimization of a novel series of potent and orally bioavailable GPR119 agonists
  Koshizawa, Tomoaki; Morimoto, Toshiharu; Watanabe, Gen; Watanabe, Toshiaki; Yamasaki, Nao; Sawada, Yoshikazu; Fukuda, Tomoaki; Okuda, Ayumu; Shibuya, Kimiyuki; Ohgiya, Tadaaki
  Bioorganic & Medicinal Chemistry Letters (2017), 27 (15), 3249-3253CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50 = 129 nM) was improved by replacing the intramol. hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compd. 12 (EC50 = 53 nM). Optimized compd. 26, which was identified by the further optimization of 12, exhibited potent activity (EC50 = 42 nM) with improved clearance in liver microsomes and induced a 33% redn. in blood glucose area under the curve at a dose of 10 mg/kg in an oral glucose tolerance test in C57BL/6N mice.
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93. 93
  Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D. A.; Davis, C. D.; Denton, R.; Han, X.; Macci, R.; Mathias, N. R.; Moench, P.; Pin, S. S.; Ren, S. X.; Schartman, R.; Signor, L. J.; Thalody, G.; Widmann, K. A.; Xu, C.; Macor, J. E.; Dubowchik, G. M. Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure. J. Med. Chem. 2008, 51, 4858– 4861, DOI: 10.1021/jm800546t
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  93
  Discovery of (R)-4-(8-Fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): A Potent Antagonist of the Human Calcitonin Gene-Related Peptide Receptor for Migraine with Rapid and Efficient Intranasal Exposure
  Degnan, Andrew P.; Chaturvedula, Prasad V.; Conway, Charles M.; Cook, Deborah A.; Davis, Carl D.; Denton, Rex; Han, Xiaojun; Macci, Robert; Mathias, Neil R.; Moench, Paul; Pin, Sokhom S.; Ren, Shelly X.; Schartman, Richard; Signor, Laura J.; Thalody, George; Widmann, Kimberly A.; Xu, Cen; Macor, John E.; Dubowchik, Gene M.
  Journal of Medicinal Chemistry (2008), 51 (16), 4858-4861CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chem. leads suffered from modest potency, significant CYP3A4 inhibition, and poor aq. soly. Herein, we describe the optimization of these leads to give 4 (BMS-694153), a mol. with outstanding potency, a favorable predictive toxicol. profile, and remarkable aq. soly. Compd. 4 has good intranasal bioavailablity in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models.
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94. 94
  Razgulin, A. V.; Mecozzi, S. Binding properties of aromatic carbon-bound fluorine. J. Med. Chem. 2006, 49, 7902– 7906, DOI: 10.1021/jm0600702
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95. 95
  (a) Lewis, R. T.; Blackaby, W. P.; Blackburn, T.; Jennings, A. S. R.; Pike, A.; Wilson, R. A.; Hallett, D. J.; Cook, S. M.; Ferris, P.; Marshall, G. R.; Reynolds, D. S.; Sheppard, W. F. A.; Smith, A. J.; Sohal, B.; Stanley, J.; Tye, S. J.; Wafford, K. A.; Atack, J. R. A pyridazine series of α2/α3 subtype selective GABA_A agonists for the treatment of anxiety. J. Med. Chem. 2006, 49, 2600– 2610, DOI: 10.1021/jm051144x
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  (b) Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.; Hallett, D.; Merchant, K. J.; Thomas, S. R. 8-Fluoroimidazo[1,2-a]pyridine: synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABA_A receptor. Bioorg. Med. Chem. Lett. 2006, 16, 1518– 1522, DOI: 10.1016/j.bmcl.2005.12.037
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  95b
  8-Fluoroimidazo[1,2-a]pyridine: Synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptor
  Humphries, Alexander C.; Gancia, Emanuela; Gilligan, Myra T.; Goodacre, Simon; Hallett, David; Merchant, Kevin J.; Thomas, Steve R.
  Bioorganic & Medicinal Chemistry Letters (2006), 16 (6), 1518-1522CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochem. mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochem. mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 2'-fluoro-5'-[8-fluoro-7-(2-hydroxy-2-propyl)imidazo[1,2-a]pyridin-3-yl]biphenyl-2-carbonitrile acts as a bioisosteric replacement for imidazopyrimidine in the GABAA receptor modulator 2'-fluoro-5'-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile.
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96. 96
  (a) Robarge, K. D.; Lee, W.; Eigenbrot, C.; Ultsch, M.; Wiesmann, C.; Heald, R.; Price, S.; Hewitt, J.; Jackson, P.; Savy, P.; Burton, B.; Choo, E. F.; Pang, J.; Boggs, J.; Yang, A.; Yang, X.; Baumgardner, M. Structure based design of novel 6,5 heterocbicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a]pyrazine G-479. Bioorg. Med. Chem. Lett. 2014, 24, 4714– 4723, DOI: 10.1016/j.bmcl.2014.08.008
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97. 97
  (a) Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Yang, X.; Richards, M.; Shipps, G. W., Jr. Discovery of a novel series of CHK1 kinase inhibitors with a distinctive hinge binding mode. ACS Med. Chem. Lett. 2012, 3, 123– 128, DOI: 10.1021/ml200249h
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  97a
  Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode
  Huang, Xiaohua; Cheng, Cliff C.; Fischmann, Thierry O.; Duca, Jose S.; Yang, Xianshu; Richards, Matthew; Shipps, Gerald W.
  ACS Medicinal Chemistry Letters (2012), 3 (2), 123-128CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection-mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2.
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  .
  (b) Huang, X.; Cheng, C. C.; Fischmann, T. O.; Duca, J. S.; Richards, M.; Tadikonda, P. K.; Reddy, P. A.; Zhao, L.; Siddiqui, M. A.; Parry, D.; Davis, N.; Seghezzi, W.; Wiswell, D.; Shipps, G. W., Jr. Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 2590– 2594, DOI: 10.1016/j.bmcl.2013.02.108
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  97b
  Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors
  Huang, Xiaohua; Cheng, Cliff C.; Fischmann, Thierry O.; Duca, Jose S.; Richards, Matthew; Tadikonda, Praveen K.; Reddy, Panduranga Adulla; Zhao, Lianyun; Arshad Siddiqui, M.; Parry, David; Davis, Nicole; Seghezzi, Wolfgang; Wiswell, Derek; Shipps, Gerald W.
  Bioorganic & Medicinal Chemistry Letters (2013), 23 (9), 2590-2594CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  N-(Piperazinylaryl) amino- and heterocyclyl-substituted thiazolecarboxamides such as N-(piperazinylpyridinyl) (oxoisoindolinyl)thiazolecarboxamide I were prepd. as selective inhibitors of checkpoint kinase 1 (CHK1). Both the identities of the amino substituent on the thiazole ring and the aryl ring connecting the piperazine moiety to the thiazolecarboxamide were varied to det. the structure-activity relationship for enzymic and cellular CHK1 inhibition and for selectivity over the related kinase CHK2. I inhibited CHK1 with IC50 values against the enzyme and against cells of 1 nM and 30 nM, resp., with > 104 selectivity for CHK1 over CHK2; the inhibition of CYP 3A4, 2D6, and 2C9 in human liver microsomes, of hERG in various assays, and of other kinases and of various G protein-coupled receptors by I was detd. The structure of a complex of I with CHK1 was detd. by X-ray crystallog.; the topol. of its binding to the ATP-binding site of CHK1 is detd.
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98. 98
  (a) Koller, A. N.; Božilović, J.; Engels, J. W.; Gohlke, H. Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs. Nucleic Acids Res. 2010, 38, 3133– 3146, DOI: 10.1093/nar/gkp1237
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  98a
  Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs
  Koller, Alrun N.; Bozilovic, Jelena; Engels, Joachim W.; Gohlke, Holger
  Nucleic Acids Research (2010), 38 (9), 3133-3146CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
  The thermodn. of base pairing is of fundamental importance. Fluorinated base analogs are valuable tools for investigating pairing interactions. To understand the influence of direct base-base interactions in relation to the role of water, pairing free energies between natural nucleobases and fluorinated analogs are estd. by potential of mean force calcns. Compared to pairing of AU and GC, pairing involving fluorinated analogs is unfavorable by 0.5-1.0 kcal mol-1. Decompg. the pairing free energies into enthalpic and entropic contributions reveals fundamental differences for Watson-Crick pairs compared to pairs involving fluorinated analogs. These differences originate from direct base-base interactions and contributions of water. Pairing free energies of fluorinated base analogs with natural bases are less unfavorable by 0.5-1.0 kcal mol-1 compared to non-fluorinated analogs. This is attributed to stabilizing C-F...H-N dipolar interactions and stronger N...H-C hydrogen bonds, demonstrating direct and indirect influences of fluorine. 7-Methyl-7H-purine and its 9-deaza analog (Z) have been suggested as members of a new class of non-fluorinated base analogs. Z is found to be the least destabilizing universal base in the context of RNA known to date. This is the first exptl. evidence for nitrogen-contg. heterocylces as bioisosteres of arom. rings bearing fluorine atoms.
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  (b) Gohlke, H.; Božilović, J.; Engels, J. W. Synthesis and properties of fluorinated nucleobases in DNA and RNA. Mol. Medicine Med. Chem. 2012, 6, 3– 32, DOI: 10.1142/9781848166363_0001
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  98b
  Synthesis and properties of fluorinated nucleobases in DNA and RNA
  Gohlke, Holger; Bozilovic, Jelena; Engels, Joachim W.
  Molecular Medicine and Medicinal Chemistry (2012), 6 (Fluorine in Pharmaceutical and Medicinal Chemistry), 3-32CODEN: MMMCCE ISSN:. (Imperial College Press)
  A review with refs. Synthesis and crystallog. studies of fluorinated non-polar nucleoside isosteres and thermodn. analyses and computer simulations of model DNA and RNAs incorporating them are reviewed.
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99. 99
  (a) Giroud, M.; Harder, M.; Kuhn, B.; Haap, W.; Trapp, N.; Schweizer, W. B.; Schirmeister, T.; Diederich, F. Fluorine scan of inhibitors of the cysteine protease human cathepsin L: dipolar and quadrupolar effects in the π-stacking of fluorinated phenyl rings on peptide amide bonds. ChemMedChem 2016, 11, 1042– 1047, DOI: 10.1002/cmdc.201600132
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  99a
  Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds
  Giroud, Maude; Harder, Michael; Kuhn, Bernd; Haap, Wolfgang; Trapp, Nils; Schweizer, W. Bernd; Schirmeister, Tanja; Diederich, Francois
  ChemMedChem (2016), 11 (10), 1042-1047CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chem. calcns. In the exptl. study, the Ph substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by addnl. interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calcns. strongly support the contributions of the mol. quadrupole moments of the fluorinated Ph rings to the π-stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π-stacking on protein amide fragments.
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  .
  (b) Giroud, M.; Ivkovic, J.; Martignoni, M.; Fleuti, M.; Trapp, N.; Haap, W.; Kuglstatter, A.; Benz, J.; Kuhn, B.; Schirmeister, T.; Diederich, F. Inhibition of the cysteine protease human cathepsin L by triazine nitriles: amide···heteroarene π-stacking interactions and chalcogen bonding in the S3 pocket. ChemMedChem 2017, 12, 257– 270, DOI: 10.1002/cmdc.201600563
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  99b
  Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide···Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket
  Giroud, Maude; Ivkovic, Jakov; Martignoni, Mara; Fleuti, Marianne; Trapp, Nils; Haap, Wolfgang; Kuglstatter, Andreas; Benz, Joerg; Kuhn, Bernd; Schirmeister, Tanja; Diederich, Francois
  ChemMedChem (2017), 12 (3), 257-270CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarene···peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory consts. (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroarom. ligands feature enhanced binding by comparison with hydrocarbon analogs. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nM) and benzothiazolyl (Ki=17 nM) ligands was enhanced by intermol. C-S···O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.
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100. 100
  Császár, P.; Császár, A. On the dipole moments of fluorobenzenes by quantum chemical methods. J. Mol. Struct.: THEOCHEM 1984, 110, 405– 407, DOI: 10.1016/0166-1280(84)80090-1
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101. 101
  van Niel, M. B.; Collins, I.; Beer, M. S.; Broughton, H. B.; Cheng, S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.; MacLeod, A. M.; Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley, M.; Russell, M. G. N.; Sohal, B.; Stanton, J. A.; Thomas, S.; Verrier, H.; Watt, A. P.; Castro, J. L. Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1_D receptor ligands with improved pharmacokinetic profiles. J. Med. Chem. 1999, 42, 2087– 2104, DOI: 10.1021/jm981133m
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  101
  Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles and 3-(3-(1-piperazinyl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles
  van Niel, Monique B.; Collins, Ian; Beer, Margaret S.; Broughton, Howard B.; Cheng, Susan K. F.; Goodacre, Simon C.; Heald, Anne; Locker, Karen L.; MacLeod, Angus M.; Morrison, Denise; Moyes, Christopher R.; O'Connor, Desmond; Pike, Andrew; Rowley, Michael; Russel, N.; Sohal, Balbinder; Stanton, Josephine A.; Thomas, Steven; Verrier, Hugh; Watt, Alan P.; Castro, Jose L.
  Journal of Medicinal Chemistry (1999), 42 (12), 2087-2104CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  It has previously been reported that a 3-(3-(1-piperazinyl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal, versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivs. with one or two fluorines in the Pr linker were developed. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compds., and this redn. of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.
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102. 102
  (a) Paulini, R.; Müller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 1788– 1805, DOI: 10.1002/anie.200462213
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  102a
  Orthogonal multipolar interactions in structural chemistry and biology
  Paulini, Ralph; Mueller, Klaus; Diederich, Francois
  Angewandte Chemie, International Edition (2005), 44 (12), 1788-1805CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The past few decades of mol. recognition studies have greatly enhanced our knowledge on apolar, ion-dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biol. receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A no. of illustrative examples of these interactions found in X-ray crystal structures of small mols. and protein-ligand complexes demonstrate their propensity and thus potential importance for both, chem. and biol. mol. recognition processes.
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  (b) Xing, L.; Keefer, C.; Brown, M. F. Fluorine multipolar interaction: towards elucidating its energetics in binding recognition. J. Fluorine Chem. 2017, 198, 47– 53, DOI: 10.1016/j.jfluchem.2016.12.013
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  102b
  Fluorine multipolar interaction: Toward elucidating its energetics in binding recognition
  Xing, Li; Keefer, Christopher; Brown, Matthew F.
  Journal of Fluorine Chemistry (2017), 198 (), 47-53CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
  Multipolar interactions have gained attention due to their roles in mol. recognition events of chem. and biol. systems. Structural evidence suggests that the fluorine multipolar interaction is a favorable mol. interaction in the paradigm of protein-ligand recognition. With an aim to understand its propensity and energetics in ligand-protein assembly, the authors mined the "Pfizer protein-ligand x-ray structure database" with three-dimensional constraints for the presence of such interactions. A set of transformation rules were applied to generate their corresponding matched mol. pairs (MMPs) that bear hydrogen(s) in place of the interacting fluorine(s). Biol. activities were retrieved from the authors' internal data warehouse for the MMPs with and without the ability to form the multipolar interaction. On the basis of the obsd. potency differences the authors detd. that the free energy gain assocd. with the fluorine multipolar interaction is relatively modest, ∼0.3-0.6 kcal/mol, and the net impact on lipophilic efficiency (LipE) is essentially neutral. A general guideline for medicinal chemists has emerged from this study, enabling a more rational employment of this type of interaction in mol. design.
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103. 103
  (a) Shi, A.; Murai, M. J.; He, S.; Lund, G.; Hartley, T.; Purohit, T.; Reddy, G.; Chruszcz, M.; Grembecka, J.; Cierpicki, T. Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 2012, 120, 4461– 4469, DOI: 10.1182/blood-2012-05-429274
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  103a
  Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia
  Shi, Aibin; Murai, Marcelo J.; He, Shihan; Lund, George; Hartley, Thomas; Purohit, Trupta; Reddy, Gireesh; Chruszcz, Maksymilian; Grembecka, Jolanta; Cierpicki, Tomasz
  Blood (2012), 120 (23), 4461-4469CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)
  Menin functions as a crit. oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resoln. crystal structure of human menin in complex with a small-mol. inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compd. binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compd. that binds to menin with low nanomolar affinity (Kd = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-mol. inhibitor.
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  .
  (b) Pollock, J.; Borkin, D.; Lund, G.; Purohit, T.; Dyguda-Kazimierowicz, E.; Grembecka, J.; Cierpicki, T. Rational design of orthogonal multipolar interactions with fluorine in protein–ligand complexes. J. Med. Chem. 2015, 58, 7465– 7474, DOI: 10.1021/acs.jmedchem.5b00975
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  103b
  Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein-Ligand Complexes
  Pollock, Jonathan; Borkin, Dmitry; Lund, George; Purohit, Trupta; Dyguda-Kazimierowicz, Edyta; Grembecka, Jolanta; Cierpicki, Tomasz
  Journal of Medicinal Chemistry (2015), 58 (18), 7465-7474CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Multipolar interactions involving fluorine and the protein backbone have been frequently obsd. in protein-ligand complexes. Such fluorine-backbone interactions may substantially contribute to the high affinity of small mol. inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin-MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogs by systematically changing the no. of fluorine atoms, and we detd. high-resoln. crystal structures of the complexes with menin. We found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin-MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine-backbone interactions in protein-ligand complexes, we developed a computational algorithm named FMAP, which calcs. fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Anal. of the menin-MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine-backbone interactions may represent a particularly attractive approach to improve inhibitors of protein-protein interactions.
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  .
  (c) Grembecka, J.; He, S.; Shi, A.; Purohit, T.; Muntean, A. G.; Sorenson, R. J.; Showalter, H. D.; Murai, M. J.; Belcher, A. M.; Hartley, T.; Hess, J. L.; Cierpicki, T. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 2012, 8, 277– 284, DOI: 10.1038/nchembio.773
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  103c
  Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia
  Grembecka, Jolanta; He, Shihan; Shi, Aibin; Purohit, Trupta; Muntean, Andrew G.; Sorenson, Roderick J.; Showalter, Hollis D.; Murai, Marcelo J.; Belcher, Amalia M.; Hartley, Thomas; Hess, Jay L.; Cierpicki, Tomasz
  Nature Chemical Biology (2012), 8 (3), 277-284CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
  Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-mol. inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compds. effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compds. provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.
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  .
  (d) Borkin, D.; Pollock, J.; Kempinska, K.; Purohit, T.; Li, X.; Wen, B.; Zhao, T.; Miao, H.; Shukla, S.; He, M.; Sun, D.; Cierpicki, T.; Grembecka, J. Property focused structure-based optimization of small molecule inhibitors of the protein–protein interaction between menin and mixed lineage leukemia (MLL). J. Med. Chem. 2016, 59, 892– 913, DOI: 10.1021/acs.jmedchem.5b01305
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  103d
  Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)
  Borkin, Dmitry; Pollock, Jonathan; Kempinska, Katarzyna; Purohit, Trupta; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Miao, Hongzhi; Shukla, Shirish; He, Miao; Sun, Duxin; Cierpicki, Tomasz; Grembecka, Jolanta
  Journal of Medicinal Chemistry (2016), 59 (3), 892-913CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Development of potent small mol. inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compds., which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compd. 1 (MI-136) to identify compds. suitable for in vivo studies in mice. This work resulted in the identification of compd. 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications.
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104. 104
  (a) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst-Sander, U.; D’Arcy, A.; Stihle, M.; Müller, K.; Diederich, F. A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F···C═O interactions. Angew. Chem., Int. Ed. 2003, 42, 2507– 2511, DOI: 10.1002/anie.200351268
  [Crossref], [CAS], Google Scholar
  104a
  A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: Evidence for C-F···C=O interactions
  Olsen, Jacob A.; Banner, David W.; Seiler, Paul; Sander, Ulrike Obst; D'Arcy, Allan; Stihle, Martine; Mueller, Klaus; Diederich, Francois
  Angewandte Chemie, International Edition (2003), 42 (22), 2507-2511CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A highly fluorophilic environment comprising the H-Cα-C=O unit of Asn 98 in the active site of thrombin was identified by X-ray crystallog. of a complex formed between the enzyme and a synthetic inhibitor (see partial X-ray structure, distances are in Angstroms). Short C-F···H-Cα and C-F···C=O contacts involving H-Cα-C=O fragments were also frequently obsd. in small-mol. X-ray crystal structures.
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  .
  (b) Olsen, J. A.; Banner, D. W.; Seiler, P.; Wagner, B.; Tschopp, T.; Obst-Sander, U.; Kansy, M.; Müller, K.; Diederich, F. Fluorine interactions at the thrombin active site: protein backbone fragments H-Cα-C═O comprise a favorable C-F environment and interactions of C-F with electrophiles. ChemBioChem 2004, 5, 666– 675, DOI: 10.1002/cbic.200300907
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  104b
  Fluorine interactions at the thrombin active site: Protein backbone fragments H-Cα-C=O comprise a favorable C-F environment and interactions of C-F with electrophiles
  Olsen, Jacob A.; Banner, David W.; Seiler, Paul; Wagner, Bjoern; Tschopp, Thomas; Obst-Sander, Ulrike; Kansy, Manfred; Mueller, Klaus; Diederich, Francois
  ChemBioChem (2004), 5 (5), 666-675CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
  In a systematic fluorine scan of a rigid inhibitor to map the fluorophilicity/fluorophobicity of the active site in thrombin, one or more F substituents were introduced into the benzyl ring reaching into the D pocket. The 4-fluorobenzyl inhibitor showed a five to tenfold higher affinity than ligands with other fluorination patterns. X-ray crystal-structure anal. of the protein-ligand complex revealed favorable C-F···H-Cα-C=O and C-F···C=O interactions of the 4-F substituent of the inhibitor with the backbone H-Cα-C=O unit of Asn98. The importance of these interactions was further corroborated by the anal. of small-mol. X-ray crystal-structure searches in the Protein Data Base (PDB) and the Cambridge Structural Database (CSD). In the C-F···C=O interactions that are obsd. for both arom. and aliph. C-F units and a variety of carbonyl and carboxyl derivs., the F atom approaches the C=O C atom preferentially along the pseudotrigonal axis of the carbonyl system. Similar orientational preferences are also seen in the dipolar interactions C-F···C≡N, C-F···C-F1 and C-F···NO2, in which the F atoms interact at subvan der Waals distances with the electrophilic centers.
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  .
  (c) Schweizer, E.; Hoffmann-Röder, A.; Olsen, J. A.; Seiler, P.; Obst-Sander, U.; Wagner, B.; Kansy, M.; Banner, D. W.; Diederich, F. Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors. Org. Biomol. Chem. 2006, 4, 2364– 2375, DOI: 10.1039/B602585D
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  There is no corresponding record for this reference.
105. 105
  Bauer, M. R.; Jones, R. N.; Baud, M. G. J.; Wilcken, R.; Boeckler, F. M.; Fersht, A. R.; Joerger, A. C.; Spencer, J. Harnessing fluorine-sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs. ACS Chem. Biol. 2016, 11, 2265– 2274, DOI: 10.1021/acschembio.6b00315
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  105
  Harnessing Fluorine-Sulfur Contacts and Multipolar Interactions for the Design of p53 Mutant Y220C Rescue Drugs
  Bauer, Matthias R.; Jones, Rhiannon N.; Baud, Matthias G. J.; Wilcken, Rainer; Boeckler, Frank M.; Fersht, Alan R.; Joerger, Andreas C.; Spencer, John
  ACS Chemical Biology (2016), 11 (8), 2265-2274CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
  Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-mol. stabilizers of this mutant. One of these mols., PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 μM, thereby increasing the melting temp. of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small mol. ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine-protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole Et anchor, which is deeply buried within the binding site in the Y220C-PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol-1 atom-1). High-resoln. crystal structures of the Y220C-ligand complexes combined with quantum chem. calcns. revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein-fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells.
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106. 106
  (a) Lou, Y.; Sweeney, Z. K.; Kuglstatter, A.; Davis, D.; Goldstein, D. M.; Han, X.; Hong, J.; Kocer, B.; Kondru, R. K.; Litman, R.; McIntosh, J.; Sarma, K.; Suh, J.; Taygerly, J.; Owens, T. D. Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s tyrosine kinase (BTK) inhibitor scaffold. Bioorg. Med. Chem. Lett. 2015, 25, 367– 371, DOI: 10.1016/j.bmcl.2014.11.030
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  106a
  Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold
  Lou, Yan; Sweeney, Zachary K.; Kuglstatter, Andreas; Davis, Dana; Goldstein, David M.; Han, Xiaochun; Hong, Junbae; Kocer, Buelent; Kondru, Rama K.; Litman, Renee; McIntosh, Joel; Sarma, Keshab; Suh, Judy; Taygerly, Joshua; Owens, Timothy D.
  Bioorganic & Medicinal Chemistry Letters (2015), 25 (2), 367-371CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a satd. bicyclic ring system yields no apparent benefit, the same operation on an unsatd. bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent mols. and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.
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  .
  (b) Lou, Y.; Han, X.; Kuglstatter, A.; Kondru, R. K.; Sweeney, Z. K.; Soth, M.; McIntosh, J.; Litman, R.; Suh, J.; Kocer, B.; Davis, D.; Park, J.; Frauchiger, S.; Dewdney, N.; Zecic, H.; Taygerly, J. P.; Sarma, K.; Hong, J.; Hill, R. J.; Gabriel, T.; Goldstein, D. M.; Owens, T. D. Structure-based drug design of RN486, a potent and selective Bruton’s tyrosine kinase (BTK) Inhibitor, for the treatment of rheumatoid arthritis. J. Med. Chem. 2015, 58, 512– 516, DOI: 10.1021/jm500305p
  [ACS Full Text ], [CAS], Google Scholar
  106b
  Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis
  Lou, Yan; Han, Xiaochun; Kuglstatter, Andreas; Kondru, Rama K.; Sweeney, Zachary K.; Soth, Michael; McIntosh, Joel; Litman, Renee; Suh, Judy; Kocer, Buelent; Davis, Dana; Park, Jaehyeon; Frauchiger, Sandra; Dewdney, Nolan; Zecic, Hasim; Taygerly, Joshua P.; Sarma, Keshab; Hong, Junbae; Hill, Ronald J.; Gabriel, Tobias; Goldstein, David M.; Owens, Timothy D.
  Journal of Medicinal Chemistry (2015), 58 (1), 512-516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alc. group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compd. I (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclin. characterization based on its favorable properties.
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  .
  (c) Lou, Y.; Lopez, F.; Jiang, Y.; Han, X.; Brotherton, C.; Billedeau, R.; Gabriel, S.; Gleason, S.; Goldstein, D. M.; Hilgenkamp, R.; Kocer, B.; Orzechowski, L.; Tan, J.; Wovkulich, P.; Wen, B.; Fry, D.; Di Lello, P.; Chen, L.; Zhang, F.-j.; Fretland, J.; Nangia, A.; Yang, T.; Owens, T. D. Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton’s tyrosine kinase (BTK). Bioorg. Med. Chem. Lett. 2017, 27, 632– 635, DOI: 10.1016/j.bmcl.2016.11.092
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  106c
  Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK)
  Lou, Yan; Lopez, Francisco; Jiang, Yongying; Han, Xiaochun; Brotherton, Chris; Billedeau, Roland; Gabriel, Steve; Gleason, Shelly; Goldstein, David M.; Hilgenkamp, Ramona; Kocer, Buelent; Orzechowski, Lucja; Tan, Jenny; Wovkulich, Peter; Wen, Bo; Fry, David; Di Lello, Paola; Chen, Lucy; Zhang, Fang-jie; Fretland, Jennifer; Nangia, Anjali; Yang, Tian; Owens, Timothy D.
  Bioorganic & Medicinal Chemistry Letters (2017), 27 (3), 632-635CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a no. of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead mols. in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compd. 1 has a value of 459 pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation assocn. of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS anal. of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compd. 7 (RN941) with significantly reduced covalent binding of 26 pmol/mg protein.
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107. 107
  Hao, G.-F.; Wang, F.; Li, H.; Zhu, X.-L.; Yang, W.-C.; Huang, L.-S.; Wu, J.-W.; Berry, E. A.; Yang, G.-F. Computational discovery of picomolar Q_o site inhibitors of cytochrome bc₁ complex. J. Am. Chem. Soc. 2012, 134, 11168– 11176, DOI: 10.1021/ja3001908
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  107
  Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 Complex
  Hao, Ge-Fei; Wang, Fu; Li, Hui; Zhu, Xiao-Lei; Yang, Wen-Chao; Huang, Li-Shar; Wu, Jia-Wei; Berry, Edward A.; Yang, Guang-Fu
  Journal of the American Chemical Society (2012), 134 (27), 11168-11176CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A crit. challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophys. method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Qo site inhibitors of the cytochrome bc1 complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compd. 4 (Ki = 881.80 nM, porcine bc1), the most potent compd. 4f displayed 20 507-fold improved binding affinity (Ki = 43.00 pM). Compd. 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Addnl., the crystal structure of compd. 4e (Ki = 83.00 pM) bound to the chicken bc1 was detd. at 2.70 Å resoln., providing a mol. basis for understanding its ultrapotency. To the authors' knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophys. screening techniques.
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108. 108
  García-LLinás, X.; Bauzá, A.; Seth, S. K.; Frontera, A. Importance of R-CF₃•••O tetrel bonding interactions in biological systems. J. Phys. Chem. A 2017, 121, 5371– 5376, DOI: 10.1021/acs.jpca.7b06052
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  There is no corresponding record for this reference.
109. 109
  Cisneros, J. A.; Robertson, M. J.; Valhondo, M.; Jorgensen, W. L. Irregularities in enzyme assays: the case of macrophage migration inhibitory factor. Bioorg. Med. Chem. Lett. 2016, 26, 2764– 2767, DOI: 10.1016/j.bmcl.2016.04.074
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  109
  Irregularities in enzyme assays: The case of macrophage migration inhibitory factor
  Cisneros, Jose A.; Robertson, Michael J.; Valhondo, Margarita; Jorgensen, William L.
  Bioorganic & Medicinal Chemistry Letters (2016), 26 (12), 2764-2767CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Inhibitors of human macrophage migration inhibitory factor (MIF) previously reported in the literature have been reexamd. by synthesis, assaying for tautomerase activity, and protein crystallog. Substantial inconsistencies between prior and current assay results are noted. They appear to arise from difficulties with the tautomerase substrates, soly. issues, and esp. covalent inhibition. Incubation time variation shows that several compds. are covalent or slow-binding inhibitors. Two protein crystal structures are provided; one confirms that a twice-discovered compd. is a covalent inhibitor.
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110. 110
  (a) Wang, F.; Travins, J.; DeLaBarre, B.; Penard-Lacronique, V.; Schalm, S.; Hansen, E.; Straley, K.; Kernytsky, A.; Liu, W.; Gliser, C.; Yang, H.; Gross, S.; Artin, E.; Saada, V.; Mylonas, E.; Quivoron, C.; Popovici-Muller, J.; Saunders, J. O.; Salituro, F. G.; Yan, S.; Murray, S.; Wei, W.; Gao, Y.; Dang, L.; Dorsch, M.; Agresta, S.; Schenkein, D. P.; Biller, S. A.; Su, S. M.; de Botton, S.; Yen, K. E. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013, 340, 622– 626, DOI: 10.1126/science.1234769
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  110a
  Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation
  Wang, Fang; Travins, Jeremy; De La Barre, Byron; Penard-Lacronique, Virginie; Schalm, Stefanie; Hansen, Erica; Straley, Kimberly; Kernytsky, Andrew; Liu, Wei; Gliser, Camelia; Yang, Hua; Gross, Stefan; Artin, Erin; Saada, Veronique; Mylonas, Elena; Quivoron, Cyril; Popovici-Muller, Janeta; Saunders, Jeffrey O.; Salituro, Francesco G.; Yan, Shunqi; Murray, Stuart; Wei, Wentao; Gao, Yi; Dang, Lenny; Dorsch, Marion; Agresta, Sam; Schenkein, David P.; Biller, Scott A.; Su, Shinsan M.; de Botton, Stephane; Yen, Katharine E.
  Science (Washington, DC, United States) (2013), 340 (6132), 622-626CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  A no. of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small mol., AGI-6780, that potently and selectively inhibits the tumor-assocd. mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymol. anal. were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
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  .
  (b) Yen, K.; Travins, J.; Wang, F.; David, M. D.; Artin, E.; Straley, K.; Padyana, A.; Gross, S.; DeLaBarre, B.; Tobin, E.; Chen, Y.; Nagaraja, R.; Choe, S.; Jin, L.; Konteatis, Z.; Cianchetta; Saunders, J. O.; Salituro, F. G.; Quivoron, C.; Opolon, P.; Bawa, O.; Saada, O.; Paci, A.; Broutin, S.; Bernard, O. A.; de Botton, S.; Marteyn, B. S.; Pilichowska, M.; Xu, Y. X.; Fang, C.; Jiang, F.; Wei, W.; Jin, S.; Silverman, L.; Liu, W.; Yang, H.; Dang, L.; Dorsch, M.; Penard-Lacronique, V.; Biller, S. A.; Su, S.-S. M. AG-221, A first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discovery 2017, 7, 478– 493, DOI: 10.1158/2159-8290.CD-16-1034
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  110b
  AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
  Yen, Katharine; Travins, Jeremy; Wang, Fang; David, Muriel D.; Artin, Erin; Straley, Kimberly; Padyana, Anil; Gross, Stefan; De La Barre, Byron; Tobin, Erica; Chen, Yue; Nagaraja, Raj; Choe, Sung; Jin, Lei; Konteatis, Zenon; Cianchetta, Giovanni; Saunders, Jeffrey O.; Salituro, Francesco G.; Quivoron, Cyril; Opolon, Paule; Bawa, Olivia; Saada, Veronique; Paci, Angelo; Broutin, Sophie; Bernard, Olivier A.; de Botton, Stephane; Marteyn, Benoit S.; Pilichowska, Monika; Xu, Ying Xia; Fang, Cheng; Jiang, Fan; Wei, Wentao; Jin, Shengfang; Silverman, Lee; Liu, Wei; Yang, Hua; Dang, Lenny; Dorsch, Marion; Penard-Lacronique, Virginie; Biller, Scott A.; Su, Shin-San Michael
  Cancer Discovery (2017), 7 (5), 478-493CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)
  Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematol. and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG prodn. and induced cellular differentiation in primary human IDH2 mutation-pos. acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clin. trials of AG-221 in patients with IDH2 mutation-pos. advanced hematol. malignancies. Significance: Mutations in IDH1/2 are identified in approx. 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclin. models and induces differentiation of malignant blasts, supporting its clin. development.
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111. 111
  Bhatia, C.; Yue, W. W.; Niesen, F.; Pilka, E.; Ugochukwu, E.; Savitsky, P.; Hozjan, V.; Roos, A. K.; Filippakopoulos, P.; Von Delft, F.; Heightman, T.; Arrowsmith, C.; Weigelt, J.; Edwards, A.; Bountra, C.; Opperman, U. 2WM3: Crystal structure of NmrA-like family domain containing protein 1 in complex with niflumic acid. Protein Data Bank, 2009, DOI: DOI: 10.2210/pdb2wm3/pdb .
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112. 112
  Blobaum, A. L.; Uddin, Md. J.; Felts, A. S.; Crews, B. C.; Rouzer, C. A.; Marnett, L. J. The 2′-trifluoromethyl analogue of indomethacin is a potent and selective COX-2 inhibitor. ACS Med. Chem. Lett. 2013, 4, 486– 490, DOI: 10.1021/ml400066a
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113. 113
  Sun, L.-Q.; Mull, E.; Zheng, B.; D’Andrea, S.; Zhao, Q.; Wang, A. X.; Sin, N.; Venables, B. L.; Sit, S.-Y.; Chen, Y.; Chen, J.; Cocuzza, A.; Bilder, D. M.; Mathur, A.; Rampulla, R.; Chen, B.-C.; Palani, T.; Ganesan, S.; Arunachalam, P. N.; Falk, P.; Levine, A.; Chen, C.; Friborg, J.; Yu, F.; Hernandez, D.; Sheaffer, A. K.; Knipe, J. O.; Han, Y.-H.; Schartman, R.; Donoso, M.; Mosure, K.; Sinz, M. W.; Zvyaga, T.; Rajamani, R.; Kish, K.; Tredup, J.; Klei, H. E.; Gao, Q.; Ng, A.; Mueller, L.; Grasela, D. M.; Adams, S.; Loy, J.; Levesque, P. C.; Sun, H.; Shi, H.; Sun, L.; Warner, W.; Li, D.; Zhu, J.; Wang, Y.-K.; Fang, H.; Cockett, M. I.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Discovery of a potent acyclic, tripeptidic, acyl sulfonamide inhibitor of hepatitis C virus NS3 protease as a back-up to asunaprevir with the potential for once-daily dosing. J. Med. Chem. 2016, 59, 8042– 8060, DOI: 10.1021/acs.jmedchem.6b00821
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  113
  Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing
  Sun, Li-Qiang; Mull, Eric; Zheng, Barbara; D'Andrea, Stanley; Zhao, Qian; Wang, Alan Xiangdong; Sin, Ny; Venables, Brian L.; Sit, Sing-Yuen; Chen, Yan; Chen, Jie; Cocuzza, Anthony; Bilder, Donna M.; Mathur, Arvind; Rampulla, Richard; Chen, Bang-Chi; Palani, Theerthagiri; Ganesan, Sivakumar; Arunachalam, Pirama Nayagam; Falk, Paul; Levine, Steven; Chen, Chaoqun; Friborg, Jacques; Yu, Fei; Hernandez, Dennis; Sheaffer, Amy K.; Knipe, Jay O.; Han, Yong-Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael W.; Zvyaga, Tatyana; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E.; Gao, Qi; Ng, Alicia; Mueller, Luciano; Grasela, Dennis M.; Adams, Stephen; Loy, James; Levesque, Paul C.; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, William; Li, Danshi; Zhu, Jialong; Wang, Ying-Kai; Fang, Hua; Cockett, Mark I.; Meanwell, Nicholas A.; McPhee, Fiona; Scola, Paul M.
  Journal of Medicinal Chemistry (2016), 59 (17), 8042-8060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir is described. The objective of this work was the identification of a drug with antiviral properties and toxicol. parameters similar to asunaprevir, but with a preclin. pharmacokinetic (PK) profile that was predictive of once-daily dosing. Crit. to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compds. that, like asunaprevir, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 from clin. trials. Structure-activity relationships (SARs) at each of the structural subsites in asunaprevir were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Addnl. modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 I.
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114. 114
  (a) Phillips, M. A.; Gujjar, R.; Malmquist, N. A.; White, J.; El Mazouni, F.; Baldwin, J.; Rathod, P. K. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite, Plasmodium falciparum. J. Med. Chem. 2008, 51, 3649– 3653, DOI: 10.1021/jm8001026
  [ACS Full Text ], [CAS], Google Scholar
  114a
  Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitors with Potent and Selective Activity against the Malaria Parasite Plasmodium falciparum
  Phillips, Margaret A.; Gujjar, Ramesh; Malmquist, Nicholas A.; White, John; El Mazouni, Farah; Baldwin, Jeffrey; Rathod, Pradipsinh K.
  Journal of Medicinal Chemistry (2008), 51 (12), 3649-3653CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor I that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogs were produced by an inexpensive three-step synthesis, and the series showed good assocn. between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC50 = 79 nM).
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  .
  (b) Gujjar, R.; Marwaha, A.; El Mazouni, F.; White, J.; White, K. L.; Creason, S.; Shackleford, D. M.; Baldwin, J.; Charman, W. N.; Buckner, F. S.; Charman, S.; Rathod, P. K.; Phillips, M. A. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J. Med. Chem. 2009, 52, 1864– 1872, DOI: 10.1021/jm801343r
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  114b
  Identification of a Metabolically Stable Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Antimalarial Activity in Mice
  Gujjar, Ramesh; Marwaha, Alka; El Mazouni, Farah; White, John; White, Karen L.; Creason, Sharon; Shackleford, David M.; Baldwin, Jeffrey; Charman, William N.; Buckner, Frederick S.; Charman, Susan; Rathod, Pradipsinh K.; Phillips, Margaret A.
  Journal of Medicinal Chemistry (2009), 52 (7), 1864-1872CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compds. contg. naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metab. in human liver microsomes and which showed prolonged exposure in mice. Compd. 21 (DSM74), contg. p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.
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  .
  (c) Deng, X.; Gujjar, R.; El Mazouni, F.; Kaminsky, W.; Malmquist, N. A.; Goldsmith, E. J.; Rathod, P. K.; Phillips, M. A. Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J. Biol. Chem. 2009, 284, 26999– 27009, DOI: 10.1074/jbc.M109.028589
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  114c
  Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds
  Deng, Xiaoyi; Gujjar, Ramesh; El Mazouni, Farah; Kaminsky, Werner; Malmquist, Nicholas A.; Goldsmith, Elizabeth J.; Rathod, Pradipsinh K.; Phillips, Margaret A.
  Journal of Biological Chemistry (2009), 284 (39), 26999-27009CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure detn. of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chem. classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small mol. crystallog., is that the triazolopyrimidines populate a resonance form that promotes charge sepn. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into species-selective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.
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  .
  (d) Coteron, J. M.; Marco, M.; Esquivias, J.; Deng, X.; White, K. L.; White, J.; Koltun, M.; El Mazouni, F.; Kokkonda, S.; Katneni, K.; Bhamidipati, R.; Shackleford, D. M.; Angulo-Barturen, I.; Ferrer, S. B.; Jiménez-Díaz, M. B.; Gamo, F.-J.; Goldsmith, E. J.; Charman, W. N.; Bathurst, I.; Floyd, D.; Matthews, D.; Burrows, J. N.; Rathod, P. K.; Charman, S. A.; Phillips, M. A. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J. Med. Chem. 2011, 54, 5540– 5561, DOI: 10.1021/jm200592f
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  114d
  Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential
  Coteron, Jose M.; Marco, Maria; Esquivias, Jorge; Deng, Xiaoyi; White, Karen L.; White, John; Koltun, Maria; El Mazouni, Farah; Kokkonda, Sreekanth; Katneni, Kasiram; Bhamidipati, Ravi; Shackleford, David M.; Angulo-Barturen, Inigo; Ferrer, Santiago B.; Jimenez-Diaz, Maria Belen; Gamo, Francisco-Javier; Goldsmith, Elizabeth J.; Charman, William N.; Bathurst, Ian; Floyd, David; Matthews, David; Burrows, Jeremy N.; Rathod, Pradipsinh K.; Charman, Susan A.; Phillips, Margaret A.
  Journal of Medicinal Chemistry (2011), 54 (15), 5540-5561CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chem. program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compd. has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compd. toward clin. candidate status.
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  .
  (e) Deng, X.; Kokkonda, S.; El Mazouni, F.; White, J.; Burrows, J. N.; Kaminsky, W.; Charman, S. A.; Matthews, D.; Rathod, P. K.; Phillips, M. A. Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. J. Med. Chem. 2014, 57, 5381– 5394, DOI: 10.1021/jm500481t
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  114e
  Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors
  Deng, Xiaoyi; Kokkonda, Sreekanth; El Mazouni, Farah; White, John; Burrows, Jeremy N.; Kaminsky, Werner; Charman, Susan A.; Matthews, David; Rathod, Pradipsinh K.; Phillips, Margaret A.
  Journal of Medicinal Chemistry (2014), 57 (12), 5381-5394CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. The authors describe a detailed anal. of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. The authors show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. The authors conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. The authors' studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
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  (f) Phillips, M. A.; Lotharius, J.; Marsh, K.; White, J.; Dayan, A.; White, K. L.; Njoroge, J. W.; El Mazouni, F.; Lao, Y.; Kokkonda, S.; Tomchick, D. R.; Deng, X.; Laird, T.; Bhatia, S. N.; March, S.; Ng, C. L.; Fidock, D. A.; Wittlin, S.; Lafuente-Monasterio, M.; Benito, F. J.; Alonso, L. M.; Martinez, M. S.; Jimenez-Diaz, M. B.; Bazaga, S. F.; Angulo-Barturen, I.; Haselden, J. N.; Louttit, J.; Cui, Y.; Sridhar, A.; Zeeman, A. M.; Kocken, C.; Sauerwein, R.; Dechering, K.; Avery, V. M.; Duffy, S.; Delves, M.; Sinden, R.; Ruecker, A.; Wickham, K. S.; Rochford, R.; Gahagen, J.; Iyer, L.; Riccio, E.; Mirsalis, J.; Bathhurst, I.; Rueckle, T.; Ding, X.; Campo, B.; Leroy, D.; Rogers, M. J.; Rathod, P. K.; Burrows, J. N.; Charman, S. A. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci. Transl. Med. 2015, 7 (296), 296ra111, DOI: 10.1126/scitranslmed.aaa6645
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  (g) Phillips, M. A.; White, K. L.; Kokkonda, S.; Deng, X.; White, J.; El Mazouni, F.; Marsh, K.; Tomchick, D. R.; Manjalanagara, K.; Rudra, K. R.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Shackleford, D. M.; Chiu, F. C. K. M.; Campbell, M.; Jimenez-Diaz, M. B.; Ferrer Bazaga, S.; Angulo-Barturen, I.; Santos Martinez, M.; Lafuente-Monasterio, M.; Kaminsky, W.; Silue, K.; Zeeman, A.-M.; Kocken, C.; Leroy, D.; Blasco, B.; Rossignol, E.; Rueckle, T.; Matthews, D.; Burrows, J. N.; Waterson, D.; Palmer, M. J.; Rathod, P. K.; Charman, S. A. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. ACS Infect. Dis. 2016, 2, 945– 957, DOI: 10.1021/acsinfecdis.6b00144
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  114g
  A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria
  Phillips, Margaret A.; White, Karen L.; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; El Mazouni, Farah; Marsh, Kennan; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N.; Marfurt, Jutta; Shackleford, David M.; Chiu, Francis C. K.; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Inigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N.; Waterson, David; Palmer, Michael J.; Rathod, Pradipsinh K.; Charman, Susan A.
  ACS Infectious Diseases (2016), 2 (12), 945-957CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
  The emergence of drug resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria and a selective inhibitor I of the Plasmodium enzyme is currently in clin. development. With the goal of identifying a backup compd. to I, the authors explored replacement of the SF5-aniline moiety of I with a series of CF3-pyridinyls, while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of II, which has improved soly., lower intrinsic clearance and increased plasma exposure after oral dosing compared to I, while maintaining a long predicted human half-life. Its improved phys. and chem. properties will allow it to be formulated more readily than I. II showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly II showed equal activity against both P. falciparum and P. vivax field isolates, while I was more active on P. falciparum. II has the potential to be developed as a single dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria leading to its advancement as a preclin. development candidate.
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115. 115
  Martin, M. P.; Zhu, J.-Y.; Lawrence, H. R.; Pireddu, R.; Luo, Y.; Alam, R.; Ozcan, S.; Sebti, S. M.; Lawrence, N. J.; Schönbrunn, E. A novel mechanism by which small molecule inhibitors induce the DFG flip in Aurora A. ACS Chem. Biol. 2012, 7, 698– 706, DOI: 10.1021/cb200508b
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  A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora A
  Martin, Mathew P.; Zhu, Jin-Yi; Lawrence, Harshani R.; Pireddu, Roberta; Luo, Yunting; Alam, Riazul; Ozcan, Sevil; Sebti, Said M.; Lawrence, Nicholas J.; Schonbrunn, Ernst
  ACS Chemical Biology (2012), 7 (4), 698-706CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
  Most protein kinases share a DFG (Asp-Phe-Gly) motif in the ATP site that can assume two distinct conformations, the active DFG-in and the inactive DFG-out states. Small mol. inhibitors able to induce the DFG-out state have received considerable attention in kinase drug discovery. Using a typical DFG-in inhibitor scaffold of Aurora A, a kinase involved in the regulation of cell division, we found that halogen and nitrile substituents directed at the N-terminally flanking residue Ala273 induced global conformational changes in the enzyme, leading to DFG-out inhibitors that are among the most potent Aurora A inhibitors reported to date. The data suggest an unprecedented mechanism of action, in which induced-dipole forces along the Ala273 side chain alter the charge distribution of the DFG backbone, allowing the DFG to unwind. As the ADFG sequence and three-dimensional structure is highly conserved, DFG-out inhibitors of other kinases may be designed by specifically targeting the flanking alanine residue with elec. dipoles.
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  (a) Clark, J.; Perrin, D. D. Prediction of the strengths of organic bases. Q. Rev., Chem. Soc. 1964, 18, 295– 320, DOI: 10.1039/qr9641800295
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  Prediction of the strengths of organic bases
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  (1964), 18 (3), 295-320 ISSN:.
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  (b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059
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  Predicting and tuning physicochemical properties in lead optimization: amine basicities
  Morgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, Klaus
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  A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
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117. 117
  Grunewald, G. L.; Seim, M. R.; Lu, J.; Makboul, M.; Criscione, K. R. Application of the Goldilocks effect to the design of potent and selective inhibitors of phenylethanolamine N-methyltransferase: balancing pK_a and steric effects in the optimization of 3-methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-fluorination. J. Med. Chem. 2006, 49, 2939– 2952, DOI: 10.1021/jm051262k
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  Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination
  Grunewald, Gary L.; Seim, Mitchell R.; Lu, Jian; Makboul, Mariam; Criscione, Kevin R.
  Journal of Medicinal Chemistry (2006), 49 (10), 2939-2952CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α2-adrenoceptor. Fluorination of the Me group lowers the pKa of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pKa results in a redn. in affinity for the α2-adrenoceptor. However, increased fluorination also results in a redn. in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochem. evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often nonselective due to significant affinity for the α2-adrenoceptor, while the latter were devoid of α2-adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pKa properties and thus have enhanced selectivity vs. the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency vs. the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the "Goldilocks Effect" analogy, the 3-fluoromethyl-THIQs are too potent (too hot) at the α2-adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α2-adrenoceptor. This seems to be the first successful use of the β-fluorination of aliph. amines to impart selectivity to a pharmacol. agent while maintaining potency at the site of interest.
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118. 118
  Spahn, V.; Del Vecchio, G.; Labuz, D.; Rodriguez-Gaztelumendi, A.; Massaly, N.; Temp, J.; Durmaz, V.; Sabri, P.; Reidelbach, M.; Machelska, H.; Weber, M.; Stein, C. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 2017, 355, 966– 969, DOI: 10.1126/science.aai8636
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  A nontoxic pain killer designed by modeling of pathological receptor conformations
  Spahn, V.; Del Vecchio, G.; Labuz, D.; Rodriguez-Gaztelumendi, A.; Massaly, N.; Temp, J.; Durmaz, V.; Sabri, P.; Reidelbach, M.; Machelska, H.; Weber, M.; Stein, C.
  Science (Washington, DC, United States) (2017), 355 (6328), 966-969CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathol. (rather than physiol.) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissocn. const., selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissocn. by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.
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119. 119
  (a) Cox, C. D.; Coleman, P. J.; Breslin, M. J.; Whitman, D. B.; Garbaccio, R. M.; Fraley, M. E.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Schaber, M. D.; Lobell, R. B.; Tao, W.; Davide, J. P.; Diehl, R. E.; Abrams, M. T.; South, V. J.; Huber, H. E.; Torrent, M.; Prueksaritanont, T.; Li, C.; Slaughter, D. E.; Mahan, E.; Fernandez-Metzler, C.; Yan, Y.; Kuo, L. C.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. J. Med. Chem. 2008, 51, 4239– 4252, DOI: 10.1021/jm800386y
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  119a
  Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer
  Cox, Christopher D.; Coleman, Paul J.; Breslin, Michael J.; Whitman, David B.; Garbaccio, Robert M.; Fraley, Mark E.; Buser, Carolyn A.; Walsh, Eileen S.; Hamilton, Kelly; Schaber, Michael D.; Lobell, Robert B.; Tao, Weikang; Davide, Joseph P.; Diehl, Ronald E.; Abrams, Marc T.; South, Vicki J.; Huber, Hans E.; Torrent, Maricel; Prueksaritanont, Thomayant; Li, Chunze; Slaughter, Donald E.; Mahan, Elizabeth; Fernandez-Metzler, Carmen; Yan, Youwei; Kuo, Lawrence C.; Kohl, Nancy E.; Hartman, George D.
  Journal of Medicinal Chemistry (2008), 51 (14), 4239-4252CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations assocd. with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor (11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compds. from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that β-fluorination modulated the pKa of the piperidine nitrogen and reduced Pgp efflux, but the resulting compd. (14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compd. 30 that has an optimal in vitro and metabolic profile. Compd. 30 (MK-0731) was recently studied in a phase I clin. trial in patients with taxane-refractory solid tumors.
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  .
  (b) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Coleman, P. J.; Garbaccio, R. M.; Fraley, M. E.; Zrada, M. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Abrams, M. T.; South, V. J.; Huber, H. E.; Kohl, N. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part V: discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein. Bioorg. Med. Chem. Lett. 2007, 17, 2697– 2702, DOI: 10.1016/j.bmcl.2007.03.006
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  McDonald, I. M.; Mate, R. A.; Zusi, F. C.; Huang, H.; Post-Munson, D. J.; Ferrante, M. A.; Gallagher, L.; Bertekap, R. L., Jr.; Knox, R. J.; Robertson, B. J.; Harden, D. G.; Morgan, D. G.; Lodge, N. J.; Dworetzky, S. I.; Olson, R. E.; Macor, J. E. Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists. Bioorg. Med. Chem. Lett. 2013, 23, 1684– 1688, DOI: 10.1016/j.bmcl.2013.01.070
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  Sun, H.; Xia, M.; Shahane, S. A.; Jadhav, A.; Austin, C. P.; Huang, R. Are hERG channel blockers also phospholipidosis inducers?. Bioorg. Med. Chem. Lett. 2013, 23, 4587– 4590, DOI: 10.1016/j.bmcl.2013.06.034
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  Are hERG channel blockers also phospholipidosis inducers?
  Sun, Hongmao; Xia, Menghang; Shahane, Sampada A.; Jadhav, Ajit; Austin, Christopher P.; Huang, Ruili
  Bioorganic & Medicinal Chemistry Letters (2013), 23 (16), 4587-4590CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Both pharmacophore models of the human ether-a-go-go-related gene (hERG) channel blockers and phospholipidosis (PLD) inducers contain a hydrophobic moiety and a hydrophilic motif/pos. charged center, so it is interesting to investigate the overlap between the ligand chem. spaces of both targets. The authors have assayed over 4000 non-redundant drug-like compds. for both their hERG inhibitory activity and PLD inducing potential in a quant. high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compds. identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compds. were pos. charged. Among the 48 compds. that induced PLD without inhibiting hERG channel, 24 compds. (50.0%) carried steroidal structures. According to the authors' results, hERG channel blockers and PLD inducers share a large chem. space. In addn., a pos. charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker.
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122. 122
  Nakajima, Y.; Inoue, T.; Nakai, K.; Mukoyoshi, K.; Hamaguchi, H.; Hatanaka, K.; Sasaki, H.; Tanaka, A.; Takahashi, F.; Kunikawa, S.; Usuda, H.; Moritomo, A.; Higashi, Y.; Inami, M.; Shirakami, S. Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3. Bioorg. Med. Chem. 2015, 23, 4871– 4883, DOI: 10.1016/j.bmc.2015.05.034
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  122
  Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3
  Nakajima, Yutaka; Inoue, Takayuki; Nakai, Kazuo; Mukoyoshi, Koichiro; Hamaguchi, Hisao; Hatanaka, Keiko; Sasaki, Hiroshi; Tanaka, Akira; Takahashi, Fumie; Kunikawa, Shigeki; Usuda, Hiroyuki; Moritomo, Ayako; Higashi, Yasuyuki; Inami, Masamichi; Shirakami, Shohei
  Bioorganic & Medicinal Chemistry (2015), 23 (15), 4871-4883CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
  Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivs. are promising candidates for treating such diseases. In chem. modification of lead compd. (I), the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addn., modulation of phys. properties such as mol. lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. The authors' optimization study gave compd. 31 (4-[[(3S,4R)-1-(5-cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide), which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
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123. 123
  Rombouts, F. J. R.; Tresadern, G.; Delgado, O.; Martínez-Lamenca, C.; Van Gool, M.; García-Molina, A.; Alonso de Diego, S. A.; Oehlrich, D.; Prokopcova, H.; Alonso, J. M.; Austin, N.; Borghys, H.; Van Brandt, S.; Surkyn, M.; De Cleyn, M.; Vos, A.; Alexander, R.; Macdonald, G.; Moechars, D.; Gijsen, H.; Trabanco, A. A. 1,4-Oxazine β-secretase 1 (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads. J. Med. Chem. 2015, 58, 8216– 8235, DOI: 10.1021/acs.jmedchem.5b01101
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  123
  1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads
  Rombouts, Frederik J. R.; Tresadern, Gary; Delgado, Oscar; Martinez-Lamenca, Carolina; Van Gool, Michiel; Garcia-Molina, Aranzazu; Alonso de Diego, Sergio A.; Oehlrich, Daniel; Prokopcova, Hana; Alonso, Jose Manuel; Austin, Nigel; Borghys, Herman; Van Brandt, Sven; Surkyn, Michel; De Cleyn, Michel; Vos, Ann; Alexander, Richard; Macdonald, Gregor; Moechars, Dieder; Gijsen, Harrie; Trabanco, Andres A.
  Journal of Medicinal Chemistry (2015), 58 (20), 8216-8235CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  1,4-Oxazines are presented, which show good in vitro inhibition in enzymic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and esp. P-glycoprotein efflux. This led to compds. which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, resp., in mouse and dog models. The amyloid lowering potential of these mols. makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.
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124. 124
  Scattolin, T.; Deckers, K.; Schoenebeck, F. Efficient synthesis of trifluoromethyl amines through a formal umpolung strategy from the bench-stable precursor (Me₄N)SCF₃. Angew. Chem., Int. Ed. 2017, 56, 221– 224, DOI: 10.1002/anie.201609480
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  Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3
  Scattolin, Thomas; Deckers, Kristina; Schoenebeck, Franziska
  Angewandte Chemie, International Edition (2017), 56 (1), 221-224CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Reported herein is the one-pot synthesis of trifluoromethylated amines at room temp. using the bench-stable (Me4N)SCF3 reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF3 with the amine, giving quant. formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N-CF3. The mildness and high functional group tolerance render the method highly attractive for the late-stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug mols.
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125. 125
  Asahina, Y.; Araya, I.; Iwase, K.; Iinuma, F.; Hosaka, M.; Ishizaki, T. Synthesis and antibacterial activity of the 4-quinolone-3-carboxylic acid derivatives having a trifluoromethyl group as a novel N-1 substituent. J. Med. Chem. 2005, 48, 3443– 3446, DOI: 10.1021/jm040204g
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126. 126
  Schow, S. R.; Mackman, R. L.; Blum, C. L.; Brooks, E.; Horsma, A. G.; Joly, A.; Kerwar, S. S.; Lee, G.; Shiffman, D.; Nelson, M. G.; Wang, X.; Wick, M. M.; Zhang, X.; Lum, R. T. Synthesis and activity of 2,6,9-trisubstituted purines. Bioorg. Med. Chem. Lett. 1997, 7, 2697– 2702, DOI: 10.1016/S0960-894X(97)10076-2
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  Miao, Z.; Zhu, L.; Dong, G.; Zhuang, C.; Wu, Y.; Wang, S.; Guo, Z.; Liu, Y.; Wu, S.; Zhu, S.; Fang, K.; Yao, J.; Li, J.; Sheng, C.; Zhang, W. A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors. J. Med. Chem. 2013, 56, 7902– 7910, DOI: 10.1021/jm400906z
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  A New Strategy To Improve the Metabolic Stability of Lactone: Discovery of (20S,21S) 21-Fluorocamptothecins as Novel, Hydrolytically Stable Topoisomerase I Inhibitors
  Miao, Zhenyuan; Zhu, Lingjian; Dong, Guoqiang; Zhuang, Chunlin; Wu, Yuelin; Wang, Shengzheng; Guo, Zizao; Liu, Yang; Wu, Shanchao; Zhu, Shiping; Fang, Kun; Yao, Jianzhong; Li, Jian; Sheng, Chunquan; Zhang, Wannian
  Journal of Medicinal Chemistry (2013), 56 (20), 7902-7910CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Lactone is a common structural motif in biol. active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin deriv., (20S,21S)-7-Cyclohexyluorocamptothecin, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. The authors' results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone.
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128. 128
  Wipf, P.; Henninger, T. C.; Geib, S. J. Methyl- and (trifluoromethyl)alkene peptide isosteres: synthesis and evaluation of their potential as β-turn promoters and peptide mimetics. J. Org. Chem. 1998, 63, 6088– 6089, DOI: 10.1021/jo981057v
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  128
  Methyl- and (Trifluoromethyl)alkene Peptide Isosteres: Synthesis and Evaluation of Their Potential as β-Turn Promoters and Peptide Mimetics
  Wipf, Peter; Henninger, Todd C.; Geib, Steven J.
  Journal of Organic Chemistry (1998), 63 (18), 6088-6089CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Enantioselective synthetic approaches were devised for L-ala-D-Ala (or enantiomeric) dipeptide alkene isostere sequences that, for the first time, included the prepn. of a (trifluoromethyl)alkene isostere. An X-ray study established that methyl- and trifluoromethyl-substituted alkenes provide conformationally considerably more highly preorganized backbone-rigidified peptide mimetics than the parent disubstituted alkenes.
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129. 129
  (a) Urban, J. J.; Tillman, B. G.; Cronin, W. A. Fluoroolefins as peptide mimetics: a computational study of structure, charge distribution, hydration, and hydrogen bonding. J. Phys. Chem. A 2006, 110, 11120– 11129, DOI: 10.1021/jp062881n
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  (b) Drouin, M.; Paquin, J.-F. Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres. Beilstein J. Org. Chem. 2017, 13, 2637– 2658
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  Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isostere
  Drouin, Myriam; Paquin, Jean-Francois
  Beilstein Journal of Organic Chemistry (2017), 13 (), 2637-2658CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  A review. Monofluoroalkenes are fluorinated motifs that can be used to replace amide bonds. In order to be incorporated into peptides, it is normally necessary to first synthesize a dipeptide where the amide bond has been replaced with a monofluoroalkene. In that context, this review will present the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isostere described since 2007. Some applications of those compds. will also be presented.
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  (c) Drouin, M.; Hamel, J.-F.; Paquin, J.-F. Synthesis of monofluoroalkenes: a leap forward. Synthesis 2018, DOI: 10.1055/s-0036-1591867
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  Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Chiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studies. Org. Biomol. Chem. 2007, 5, 1151– 1157, DOI: 10.1039/b701559c
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  Chiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studies
  Couve-Bonnaire, Samuel; Cahard, Dominique; Pannecoucke, Xavier
  Organic & Biomolecular Chemistry (2007), 5 (8), 1151-1157CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  A review. The replacement of the amide bond in a peptide backbone is a promising strategy in peptidomimetic drug research. Over the various amide bond surrogates, the fluoroolefin moiety has been successfully developed as an effective mimic. Today, fluorine-contg. compds. account for a large proportion of new active mols. in life sciences. The synthesis of fluoroolefin peptide mimics is not a trivial task and innovative approaches often need to be addressed, in particular for the stereocontrol of the double bond configuration and the chiral centers adjacent to the fluoroalkene. These fluorinated peptidomimetics have been synthesized and evaluated as metabolically stable and/or conformationally constrained analogs of enzyme inhibitors, and as tools for probing the function, structure, and binding process of receptors.
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131. 131
  Nadon, J.-F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T. H.; Blais, V.; Guérin, B.; Gendron, L.; Dory, Y. L. Synthesis of Gly-ψ[(Z)CF═CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimetic. ACS Chem. Neurosci. 2017, 8, 40– 49, DOI: 10.1021/acschemneuro.6b00163
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  131
  Synthesis of Gly-ψ[(Z)CF=CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimetic
  Nadon, Jean-Francois; Rochon, Kristina; Grastilleur, Sebastien; Langlois, Guillaume; Dao, Thi Thanh Ha; Blais, Veronique; Guerin, Brigitte; Gendron, Louis; Dory, Yves L.
  ACS Chemical Neuroscience (2017), 8 (1), 40-49CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  A new Leu-enkephalin peptidomimetic designed to explore the hydrogen bond acceptor ability of the third peptide bond has been prepd. and studied. This new analog is produced by replacing the third amide of Leu-enkephalin with a fluoroalkene. An efficient and innovative synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(Z)CF=CH]-Phe-OH is described. The key step involves the alkylation of a tin dienolate from the less hindered face of its chiral sulfonamide auxiliary derived from camphor. Once its synthesis was complete, its incorporation into the peptidomimetic sequence was achieved on a solid support with chlorotrityl resin following the Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) strategy. The peptidomimetic was characterized using competition binding with [125I]-deltorphin I on membrane exts. of HEK293 cells expressing the mouse delta opioid receptor (DOPr) and based on its abilities to inhibit the elec. induced contractions of the mouse vas deferens and to activate the ERK1/2 signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous observations, our findings strongly suggest that the third amide bond of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr. Consequently, this amide bond can be successfully replaced by an ester, a thioamide, or a fluoroalkene without greatly impacting the binding or biol. activity of the corresponding analogs. The lipophilicity (LogD7.4) of the active analog was also measured. It appears that fluoroalkenes are almost as efficient at increasing the lipophilicity as normal alkenes.
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132. 132
  Karad, S. N.; Pal, M.; Crowley, R. S.; Prisinzano, T. E.; Altman, R. A. Synthesis and opioid activity of Tyr¹-Ψ(Z)CF═CH]-Gly² and Tyr¹-Ψ(S)/(R)CF₃CH-NH]-Gly² Leu enkephalin fluorinated peptidomimetics. ChemMedChem 2017, 12, 571– 576, DOI: 10.1002/cmdc.201700103
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  Rogers, M. T. The electric moments of some unsaturated aldehydes, ethers and halogen compounds. J. Am. Chem. Soc. 1947, 69, 1243– 1246, DOI: 10.1021/ja01198a003
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134. 134
  (a) Kobayakawa, T.; Narumi, T.; Tamamura, H. Remote stereoinduction in the organocuprate-mediated allylic alkylation of allylic gem-dichlorides: highly diastereoselective synthesis of (Z)-chloroalkene dipeptide isosteres. Org. Lett. 2015, 17, 2302– 2305, DOI: 10.1021/acs.orglett.5b00611
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  (b) Waelchli, R.; Gamse, R.; Bauer, W.; Lier, E.; Feyen, J. H. M. Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogues of hPTH(1–36) fragment. Bioorg. Med. Chem. Lett. 1996, 6, 1151– 1156, DOI: 10.1016/0960-894X(96)00188-6
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  Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogs of hPTH(1-36) fragment
  Waelchli, Rudolf; Gamse, Rainer; Bauer, Wilfried; Meigel, Harald; Lier, Edouard; Feyen, Jean H. M.
  Bioorganic & Medicinal Chemistry Letters (1996), 6 (10), 1151-1156CODEN: BMCLE8; ISSN:0960-894X. (Elsevier)
  A series of human parathyroid hormone (1-36) [hPTH(1-36)] analogs were prepd. to study the role of the first peptide bond between residues Ser1-Val2. Some of these analogs were found to show high affinity binding in intact opossum kidney (OK-1) cells and were very active in their ability to stimulate adenylate cyclase prodn. in intact OK-1 cells, rat UMR-106-06 osteosarcoman cells and SaOS-2 human osteosarcoma cells.
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  (c) Kobayakawa, T.; Matsuzaki, Y.; Hozumi, K.; Nomura, W.; Nomizu, M.; Tamamura, H. Synthesis of a Chloroalkene dipeptide isostere-containing peptidomimetic and its biological application. ACS Med. Chem. Lett. 2018, 9, 6– 10, DOI: 10.1021/acsmedchemlett.7b00234
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  Synthesis of a chloroalkene dipeptide isostere-containing peptidomimetic and its biological application
  Kobayakawa, Takuya; Matsuzaki, Yudai; Hozumi, Kentaro; Nomura, Wataru; Nomizu, Motoyoshi; Tamamura, Hirokazu
  ACS Medicinal Chemistry Letters (2018), 9 (1), 6-10CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  The first rapid and efficient chem. synthesis of a cyclic Arg-Gly-Asp (RGD) peptide contg. a chloroalkene dipeptide isostere (CADI) is reported. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI was obtained utilizing diastereoselective allylic alkylation as a key reaction. This CADI was also transformed into an N-Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) protected CADI in a few steps. The CADI was used in Fmoc-based solid-phase peptide synthesis. The first synthesis of a CADI-contg. cyclic RGD peptide was successful, and the synthesized CADI-contg. peptidomimetic was found to be a more potent inhibitor against integrin-mediated cell attachment than the parent cyclic peptide.
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135. 135
  Edmondson, S. D.; Wei, L.; Xu, J.; Shang, J.; Xu, S.; Pang, J.; Chaudhary, A.; Dean, D. C.; He, H.; Leiting, B.; Lyons, K. A.; Patel, R. A.; Patel, S. B.; Scapin, G.; Wu, J. K.; Beconi, M. G.; Thornberry, N. A.; Weber, A. E. Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 2409– 2413, DOI: 10.1016/j.bmcl.2008.02.050
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  135
  Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors
  Edmondson, Scott D.; Wei, Lan; Xu, Jinyou; Shang, Jackie; Xu, Shiyao; Pang, Jianmei; Chaudhary, Ashok; Dean, Dennis C.; He, Huaibing; Leiting, Barbara; Lyons, Kathryn A.; Patel, Reshma A.; Patel, Sangita B.; Scapin, Giovanna; Wu, Joseph K.; Beconi, Maria G.; Thornberry, Nancy A.; Weber, Ann E.
  Bioorganic & Medicinal Chemistry Letters (2008), 18 (7), 2409-2413CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
  The synthesis, selectivity, rat pharmacokinetic profile, and drug metab. profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
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136. 136
  (a) Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics. Bioorg. Med. Chem. Lett. 2012, 22, 2938– 2942, DOI: 10.1016/j.bmcl.2012.02.051
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  136a
  Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics
  Chang, Wonsuk; Mosley, Ralph T.; Bansal, Shalini; Keilman, Meg; Lam, Angela M.; Furman, Phillip A.; Otto, Michael J.; Sofia, Michael J.
  Bioorganic & Medicinal Chemistry Letters (2012), 22 (8), 2938-2942CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-mol. hydrogen bonds were a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin contg. inhibitor exhibited picomolar activity (EC50 = 79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
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  .
  (b) Belema, M.; Lopez, O. D.; Bender, J. A.; Romine, J. L.; St. Laurent, D. R.; Langley, D. R.; Lemm, J. A.; O’Boyle, D. R., II; Sun, J.-H.; Wang, C.; Fridell, R. A.; Meanwell, N. A. The discovery and development of hepatitis C virus NS5A replication complex inhibitors. J. Med. Chem. 2014, 57, 1643– 1672, DOI: 10.1021/jm401793m
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  136b
  Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors
  Belema, Makonen; Lopez, Omar D.; Bender, John A.; Romine, Jeffrey L.; St. Laurent, Denis R.; Langley, David R.; Lemm, Julie A.; O'Boyle, Donald R., II; Sun, Jin-Hua; Wang, Chunfu; Fridell, Robert A.; Meanwell, Nicholas A.
  Journal of Medicinal Chemistry (2014), 57 (5), 1643-1672CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chem. studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compds. currently in clin. trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogs that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clin. trials with HCV NS5A RCIs.
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137. 137
  Hollenstein, M.; Leumann, C. J. Fluorinated olefinic peptide nucleic acid: synthesis and pairing properties with complementary DNA. J. Org. Chem. 2005, 70, 3205– 3217, DOI: 10.1021/jo047753e
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  137
  Fluorinated Olefinic Peptide Nucleic Acid: Synthesis and Pairing Properties with Complementary DNA
  Hollenstein, Marcel; Leumann, Christian J.
  Journal of Organic Chemistry (2005), 70 (8), 3205-3217CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The fluorinated olefinic peptide nucleic acid (F-OPA) system was designed as a peptide nucleic acid (PNA) analog in which the base carrying amide moiety was replaced by an isostructural and isoelectrostatic fluorinated C-C double bond, locking the nucleobases in one of the two possible rotameric forms. By comparison of the base-pairing properties of this analog with its nonfluorinated analog OPA and PNA, the authors attempted a closer understanding of the role of this amide function in complementary DNA recognition. Here, the synthesis of the F-OPA monomer building blocks contg. the nucleobases A, T, and G according to the MMTr/Acyl protecting group scheme is presented. Key steps are a selective desymmetrization of the double bond in the monomer precursor via lactonization as well as a highly regioselective Mitsunobu reaction for the introduction of the bases. PNA decamers contg. single F-OPA mutations and fully modified F-OPA decamers and pentadecamers contg. the bases A and T were synthesized by solid-phase peptide chem., and their hybridization properties with complementary parallel and antiparallel DNA were assessed by UV melting curves and CD spectroscopic methods. The stability of the duplexes formed by the decamers contg. single (Z)-F-OPA modifications with parallel and antiparallel DNA was found to be strongly dependent on their position in the sequence with Tm values ranging from +2.4 to -8.1°/modification as compared to PNA. Fully modified F-OPA decamers and pentadecamers were found to form parallel duplexes with complementary DNA with reduced stability compared to PNA or OPA. An asym. F-OPA pentadecamer was found to form a stable self-complex (Tm ∼ 65°) of unknown structure. The generally reduced affinity to DNA may therefore be due to an increased propensity for self-aggregation.
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138. 138
  (a) Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.; Hayes, M. J.; Jones, D. E.; Neumann, W. L.; Wood, R. S.; Lachance, R. M.; Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. J. Med. Chem. 2003, 46, 4050– 4062, DOI: 10.1021/jm030131l
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  There is no corresponding record for this reference.
  .
  (b) Parlow, J. J.; Stevens, A. M.; Stegeman, R. A.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. Synthesis and crystal structures of substituted benzenes and benzoquinones as tissue factor VIIa inhibitors. J. Med. Chem. 2003, 46, 4297– 4312, DOI: 10.1021/jm030233b
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  138b
  Synthesis and Crystal Structures of Substituted Benzenes and Benzoquinones as Tissue Factor VIIa Inhibitors
  Parlow, John J.; Stevens, Anna M.; Stegeman, Roderick A.; Stallings, William C.; Kurumbail, Ravi G.; South, Michael S.
  Journal of Medicinal Chemistry (2003), 46 (20), 4297-4312CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Several multistep syntheses of substituted benzenes are reported. The benzene analogs were designed such that their substitution pattern would occupy and interact with the S1, S2, and S3 pockets of the tissue Factor VIIa enzyme. A variety of chem. transformations including nucleophilic addns., reductive aminations, Stille couplings, and polymer-assisted soln.-phase (PASP) techniques were used to prep. key intermediates and final products. The initial analogs identified some weakly active compds. which ultimately led to a 340 nM (IC50) tissue Factor VIIa inhibitor with selectivity over other related enzymes. The structure-activity relationship of these inhibitors and the synthetic progression from the discovery of the lead compd. to the development of potent analogs will be discussed. The X-ray crystal structures of 3'-amino-N-[[4-(aminoiminomethyl)phenyl]methyl]-3-fluoro-4-[(1-methylethyl)amino]-[1,1'-biphenyl]-2-acetamide and N-[[4-(aminoiminomethyl)phenyl]methyl]-5-[(1-methylethyl)amino]-3,6-dioxo-2-phenyl-1,4-cyclohexadiene-1-acetamide inhibitors complexed with the TF/VIIa enzyme will also be described. Other compds. thus prepd. and screened included N-[[4-(aminoiminomethyl)phenyl]methyl]-3-hydroxy-4-[(1-methylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-3-hydroxy-4-[(2-phenylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-3-fluoro-4-[(2-phenylethyl)amino]-[1,1'-biphenyl]-2-acetamide, N-[[4-(aminoiminomethyl)phenyl]methyl]-2,6-difluoro-3-[[(phenylmethyl)sulfonyl]amino]benzeneacetamide.
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  .
  (c) Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; South, M. S. Synthesis and X-ray crystal structures of substituted fluorobenzene and benzoquinone inhibitors of the tissue factor VIIa complex. Bioorg. Med. Chem. Lett. 2003, 13, 3721– 3725, DOI: 10.1016/j.bmcl.2003.08.002
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  (d) Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C.; South, M. S. Design, synthesis, and crystal structure of selective 2-pyridone tissue factor VIIa inhibitors. J. Med. Chem. 2003, 46, 4696– 4701, DOI: 10.1021/jm0301686
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  138d
  Design, Synthesis, and Crystal Structure of Selective 2-Pyridone Tissue Factor VIIa Inhibitors
  Parlow, John J.; Kurumbail, Ravi G.; Stegeman, Roderick A.; Stevens, Anna M.; Stallings, William C.; South, Michael S.
  Journal of Medicinal Chemistry (2003), 46 (22), 4696-4701CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Targeted 2-pyridones were selected as tissue factor VIIa inhibitors and prepd. from 2,6-dibromopyridine via a multistep synthesis. A variety of chem. transformations, including regioselective nucleophilic addn., selective nitrogen alkylation, and a Suzuki coupling, afforded the targeted tissue factor VIIa inhibitors. The pyridone core was selected as a replacement for the pyrazinone core of noncovalent tissue Factor VIIa inhibitors and designed such that their substitution pattern would occupy and interact with the S1, S2, and S3 pockets of the tissue factor VIIa enzyme. These compds. were tested in several serine protease enzyme assays involved in the coagulation cascade exhibiting modest activity on tissue factor VIIa with excellent selectivity over thrombin and Factor Xa. Finally, an X-ray crystal structure of one inhibitor bound to tissue factor VIIa was obtained and will be described. Compds. thus prepd. and tested were 3-amino-5-[1-[2-[[[4-(aminoiminomethyl)phenyl]methyl]amino]-2-oxoethyl]-1,6-dihydro-5-[(1-methylethyl)amino]-6-oxo-2-pyridinyl]benzoic acid and N-[[4-(aminoiminomethyl)phenyl]methyl]-6-(3,5-diaminophenyl)-3-[(1-methylethyl)amino]-2-oxo-1(2H)-pyridineacetamide.
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139. 139
  (a) Lee, L.; Kreutter, K. D.; Pan, W.; Crysler, C.; Spurlino, J.; Player, M. R.; Tomczuk, B.; Lu, T. 2-(2-Chloro-6-fluorophenyl)-acetamides as potent thrombin inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 6266– 6269, DOI: 10.1016/j.bmcl.2007.09.013
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  (b) Kreutter, K. D.; Lu, T.; Lee, L.; Giardino, E. C.; Patel, S.; Huang, H.; Xu, G.; Fitzgerald, M.; Haertlein, B. J.; Mohan, V.; Crysler, C.; Eisennagel, S.; Dasgupta, M.; McMillan, M.; Spurlino, J. C.; Huebert, N. D.; Maryanoff, B. E.; Tomczuk, B. E.; Damiano, B. P.; Player, M. R. Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif. Bioorg. Med. Chem. Lett. 2008, 18, 2865– 2870, DOI: 10.1016/j.bmcl.2008.03.087
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  (c) Nantermet, P. G.; Burgey, C. S.; Robinson, K. A.; Pellicore, J. M.; Newton, C. L.; Deng, J. M.; Selnick, H. G.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Miller-Stein, C.; White, R. B.; Wong, B.; McMasters, D. R.; Wallace, A. A.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P.; Lyle, T. A. P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold. Bioorg. Med. Chem. Lett. 2005, 15, 2771– 2775, DOI: 10.1016/j.bmcl.2005.03.110
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  (d) Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Sanderson, P. E. J.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P. D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J. C.; Stranieri, M. T.; Holahan, M. A.; Sitko, G. R.; Cook, J. J.; McMasters, D. R.; McDonough, C. M.; Sanders, W. M.; Wallace, A. A.; Clayton, F. C.; Bohn, D.; Leonard, Y. M.; Detwiler, T. J., Jr.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P. Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. J. Med. Chem. 2003, 46, 461– 473, DOI: 10.1021/jm020311f
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140. 140
  (a) Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. The pKBHX database: toward a better understanding of hydrogen-bond basicity for medicinal chemists. J. Med. Chem. 2009, 52, 4073– 4086, DOI: 10.1021/jm801331y
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  140a
  The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal Chemists
  Laurence, Christian; Brameld, Ken A.; Graton, Jerome; Le Questel, Jean-Yves; Renault, Eric
  Journal of Medicinal Chemistry (2009), 52 (14), 4073-4086CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. The pKBHX database is presented, which corresponds to three main fields of data: hydrogen bond donor identification, thermodn. data and spectroscopic data. The pKBHX scale of hydrogen donor basicity differs considerable from the pKBH+ scale of proton transfer basicity. The hydrogen bond basicities of functional groups relevant to medicinal chem. and drug design is reviewed.
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  (b) Kenny, P. W.; Montanari, C. A.; Prokopczyk, I. M.; Ribeiro, J. F.; Sartori, G. R. Hydrogen bond basicity prediction for medicinal chemistry design. J. Med. Chem. 2016, 59, 4278– 4288, DOI: 10.1021/acs.jmedchem.5b01946
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  140b
  Hydrogen Bond Basicity Prediction for Medicinal Chemistry Design
  Kenny, Peter W.; Montanari, Carlos A.; Prokopczyk, Igor M.; Ribeiro, Jean F. R.; Sartori, Geraldo Rodrigues
  Journal of Medicinal Chemistry (2016), 59 (9), 4278-4288CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Hydrogen bonding is discussed in the context of medicinal chem. design. Minimized mol. electrostatic potential (Vmin) is shown to be an effective predictor of hydrogen bond basicity (pKBHX), and predictive models are presented for a no. of hydrogen bond acceptor types relevant to medicinal chem. The problems posed by the presence of nonequivalent hydrogen bond acceptor sites in mol. structures are addressed by using nonlinear regression to fit measured pKBHX to calcd. Vmin. Predictions are made for hydrogen bond basicity of fluorine in situations where relevant exptl. measurements are not available. It is shown how predicted pKBHX can be used to provide insight into the nature of bioisosterism and to profile heterocycles. Examples of pKBHX prediction for mol. structures with multiple, nonequivalent hydrogen bond acceptors are presented.
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  .
  (c) Pierce, A. C.; Sandretto, K. L.; Bemis, G. W. Kinase inhibitors and the case for CH···O hydrogen bonds in protein-ligand binding. Proteins: Struct., Funct., Genet. 2002, 49, 567– 576, DOI: 10.1002/prot.10259
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  Kinase inhibitors and the case for CH···O hydrogen bonds in protein-ligand binding
  Pierce, Albert C.; Sandretto, Kathryn L.; Bemis, Guy W.
  Proteins: Structure, Function, and Genetics (2002), 49 (4), 567-576CODEN: PSFGEY; ISSN:0887-3585. (Wiley-Liss, Inc.)
  Although the hydrogen bond is known to be an important mediator of intermol. interactions, there has yet to be an anal. of the role of CH···O hydrogen bonds in protein-ligand complexes. In this work, we present evidence for such nonstandard hydrogen bonds from a survey of arom. ligands in 184 kinase crystal structures and 358 high-resoln. structures from the Protein Data Bank. CH groups adjacent to the pos. charged nitrogen of nicotinamide exhibit geometric preferences strongly suggestive of hydrogen bonding interactions, as do heterocyclic CH groups in kinase ligands, while other arom. CH groups do not exhibit these characteristics. Ab initio calcns. reveal a considerable range of CH···O hydrogen bonding potentials among different arom. ring systems, with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. These results provide compelling evidence for the existence of CH···O hydrogen bonds in protein-ligand interactions, as well as information on the relative strength of various arom. CH donors. Such knowledge will be of considerable value in protein modeling, ligand design, and structure-activity anal.
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141. 141
  Anilkumar, G. N.; Lesburg, C. A.; Selyutin, O.; Rosenblum, S. B.; Zeng, Q.; Jiang, Y.; Chan, T.-Y.; Pu, H.; Vaccaro, H.; Wang, L.; Bennett, F.; Chen, K. X.; Duca, J.; Gavalas, S.; Huang, Y.; Pinto, P.; Sannigrahi, M.; Velazquez, F.; Venkatraman, S.; Vibulbhan, B.; Agrawal, S.; Butkiewicz, N.; Feld, B.; Ferrari, E.; He, Z.; Jiang, C.-k.; Palermo, R. E.; Mcmonagle, P.; Huang, H.-C.; Shih, N.-Y.; Njoroge, G.; Kozlowski, J. A. I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles. Bioorg. Med. Chem. Lett. 2011, 21, 5336– 5341, DOI: 10.1016/j.bmcl.2011.07.021
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  141
  I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocycles
  Anilkumar, Gopinadhan N.; Lesburg, Charles A.; Selyutin, Oleg; Rosenblum, Stuart B.; Zeng, Qingbei; Jiang, Yueheng; Chan, Tin-Yau; Pu, Haiyan; Vaccaro, Henry; Wang, Li; Bennett, Frank; Chen, Kevin X.; Duca, Jose; Gavalas, Stephen; Huang, Yuhua; Pinto, Patrick; Sannigrahi, Mousumi; Velazquez, Francisco; Venkatraman, Srikanth; Vibulbhan, Bancha; Agrawal, Sony; Butkiewicz, Nancy; Feld, Boris; Ferrari, Eric; He, Zhiqing; Jiang, Chuan-kui; Palermo, Robert E.; McMonagle, Patricia; Huang, H.-C.; Shih, Neng-Yang; Njoroge, George; Kozlowski, Joseph A.
  Bioorganic & Medicinal Chemistry Letters (2011), 21 (18), 5336-5341CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead I (NS5B IC50 = 0.9 μM, replicon EC50 >100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in lead carboxyindoles II (NS5B IC50 = 0.032 μM, replicon EC50 = 1.4 μM) and III (NS5B IC50 = 0.017 μM, replicon EC50 = 0.3 μM) with improved enzyme and replicon activity.
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142. 142
  Adams, M. E.; Wallace, M. B.; Kanouni, T.; Scorah, N.; O’Connell, S. M.; Miyake, H.; Shi, L.; Halkowycz, P.; Zhang, L.; Dong, Q. Design and synthesis of orally available MEK inhibitors with potent in vivo antitumor efficacy. Bioorg. Med. Chem. Lett. 2012, 22, 2411– 2414, DOI: 10.1016/j.bmcl.2012.02.026
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143. 143
  (a) Isshiki, Y.; Kohchi, Y.; Iikura, H.; Matsubara, Y.; Asoh, K.; Murata, T.; Kohchi, M.; Mizuguchi, E.; Tsujii, S.; Hattori, K.; Miura, T.; Yoshimura, Y.; Aida, S.; Miwa, M.; Saitoh, R.; Murao, N.; Okabe, H.; Belunis, C.; Janson, C.; Lukacs, C.; Schück, V.; Shimma, N. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg. Med. Chem. Lett. 2011, 21, 1795– 1801, DOI: 10.1016/j.bmcl.2011.01.062
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  (b) Leijen, S.; Middleton, M. R.; Tresca, P.; Kraeber-Bodéré, F.; Dieras, V.; Scheulen, M. E.; Gupta, A.; Lopez-Valverde, V.; Xu, Z. X.; Rueger, R.; Tessier, J. J.; Shochat, E.; Blotner, S.; Naegelen, V. M.; Schellens, J. H.; Eberhardt, W. E. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin. Cancer Res. 2012, 18, 4794– 4805, DOI: 10.1158/1078-0432.CCR-12-0868
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  143b
  Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors
  Leijen, Suzanne; Middleton, Mark R.; Tresca, Patricia; Kraeber-Bodere, Francoise; Dieras, Veronique; Scheulen, Max E.; Gupta, Avinash; Lopez-Valverde, Vanesa; Xu, Zhi-Xin; Rueger, Ruediger; Tessier, Jean J. L.; Shochat, Eliezer; Blotner, Steve; Naegelen, Valerie Meresse; Schellens, Jan H. M.; Eberhardt, Wilfried Ernst Erich
  Clinical Cancer Research (2012), 18 (17), 4794-4805CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
  Purpose: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its max. tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-wk cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. Results: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approx. 4 h. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC50). Of the patients evaluable for response, clin. benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a redn. in fluorodeoxyglucose uptake by positron emission tomog. between baseline and day 15. Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. Clin Cancer Res; 18(17); 4794-805. ©2012 AACR.
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144. 144
  Ohren, J. F.; Chen, H.; Pavlovsky, A.; Whitehead, C.; Zhang, E.; Kuffa, P.; Yan, C.; McConnell, P.; Spessard, C.; Banotai, C.; Mueller, W. T.; Delaney, A.; Omer, C.; Sebolt-Leopold, J.; Dudley, D. T.; Leung, I. K.; Flamme, C.; Warmus, J.; Kaufman, M.; Barrett, S.; Tecle, H.; Hasemann, C. A. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 2004, 11, 1192– 1197, DOI: 10.1038/nsmb859
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  Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition
  Ohren, Jeffrey F.; Chen, Huifen; Pavlovsky, Alexander; Whitehead, Christopher; Zhang, Erli; Kuffa, Peter; Yan, Chunhong; McConnell, Patrick; Spessard, Cindy; Banotai, Craig; Mueller, W. Thomas; Delaney, Amy; Omer, Charles; Sebolt-Leopold, Judith; Dudley, David T.; Leung, Iris K.; Flamme, Cathlin; Warmus, Joseph; Kaufman, Michael; Barrett, Stephen; Tecle, Haile; Hasemann, Charles A.
  Nature Structural & Molecular Biology (2004), 11 (12), 1192-1197CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  MEK1 and MEK2 kinases are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK MAP kinase (MAPK) signaling pathway. Approx. 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here, the authors present the x-ray crystal structures of human MEK1 and MEK2 kinases, each detd. as a ternary complex with MgATP and an inhibitor to a resoln. of 2.4 and 3.2 Å, resp. The structures revealed that MEK1 and MEK2 each had a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitors induced several conformational changes in the unphosphorylated MEK1 and MEK2 kinases that locked them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.
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145. 145
  Kong, J. W.; Hamann, L. G.; Ruppar, D. A.; Edwards, J. P.; Marschke, K. B.; Jones, T. K. Effects of isosteric pyridone replacements in androgen receptor antagonists based on 1,2-dihydro- and 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinolones. Bioorg. Med. Chem. Lett. 2000, 10, 411– 414, DOI: 10.1016/S0960-894X(00)00010-X
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  Qiu, J.; Stevenson, S. H.; O'Beirne, M. J.; Silverman, R. B. 2,6-Difluorophenol as a bioisostere of a carboxylic acid: bioisosteric analogues of γ-aminobutyric acid. J. Med. Chem. 1999, 42, 329– 332, DOI: 10.1021/jm980435l
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147. 147
  (a) Nicolaou, I.; Zika, C.; Demopoulos, V. J. [1-(3,5-Difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone as a bioisostere of a carboxylic acid aldose reductase inhibitor. J. Med. Chem. 2004, 47, 2706– 2709, DOI: 10.1021/jm031060t
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  (b) Alexiou, P.; Demopoulos, V. J. A diverse series of substituted benzenesulfonamides as aldose reductase inhibitors with antioxidant activity: design, synthesis, and in vitro activity. J. Med. Chem. 2010, 53, 7756– 7766, DOI: 10.1021/jm101008m
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  147b
  A Diverse Series of Substituted Benzenesulfonamides as Aldose Reductase Inhibitors with Antioxidant Activity: Design, Synthesis, and in Vitro Activity
  Alexiou, Polyxeni; Demopoulos, Vassilis J.
  Journal of Medicinal Chemistry (2010), 53 (21), 7756-7766CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Based on bioisosteric principles, 2,6-difluorophenol and tetrazole, methylsulfonylamide, and isoxazolidin-3-one phenylsulfonamide derivs. were synthesized and tested in vitro in protocols primarily related to the long-term diabetic complications. Most of the compds. were found as aldose reductase inhibitors (ARIs) at IC50 < 100 μM, while the introduction of the 4-bromo-2-fluorobenzyl group in a phenylsulfonamidodifluorophenol structure resulted in I, presenting a submicromolar inhibitory profile. However, the derivs. of tetrazole, methylsulfonylamine, and the (R)-enantiomer of isoxazolidin-3-one did not exhibit appreciable aldose reductase inhibitors (ARI) activity. The selectivity of the active ARIs is also discussed. Furthermore, the synthesized compds. exhibit potent antioxidant potential (homogeneous and heterogeneous systems).
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  (a) Burkhart, J. P.; Weintraub, P. M.; Gates, C. A.; Resvick, R. J.; Vaz, R. J.; Friedrich, D.; Angelastro, M. R.; Bey, P.; Peet, N. P. Novel steroidal vinyl fluorides as inhibitors of steroid C₁₇₍₂₀₎ lyase. Bioorg. Med. Chem. 2002, 10, 929– 934, DOI: 10.1016/S0968-0896(01)00354-6
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  Li, X.; Singh, S. M.; Luu-The, V.; Côté, J.; Laplante, S.; Labrie, F. Vinyl fluoride as a mimic of the ’intermediate’ enol form in the 5α-reductase transformation: synthesis and in vitro activity of (N-1′, 1′-dimethylethyl)-3-haloandrost-3,5-diene-17β-carboxamides. Bioorg. Med. Chem. 1996, 4, 55– 60, DOI: 10.1016/0968-0896(95)00160-3
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  Pirrung, M. C.; Ha, H.-J.; Holmes, C. P. Purification and inhibition of spinach αβ,-dihydroxyacid dehydratase. J. Org. Chem. 1989, 54, 1543– 1548, DOI: 10.1021/jo00268a014
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  Dixon, D. A.; Fukunaga, T.; Smart, B. E. Geometries and energies of the fluoroethylenes. J. Am. Chem. Soc. 1986, 108, 1585– 1588, DOI: 10.1021/ja00267a031
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  Leriche, C.; He, X.; Chang, C.-w. T.; Liu, H.-w. Reversal of the apparent regiospecificity of NAD(P)H-dependent hydride transfer: the properties of the difluoromethylene group, a carbonyl mimic. J. Am. Chem. Soc. 2003, 125, 6348– 6349, DOI: 10.1021/ja021487+
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  Reversal of the Apparent Regiospecificity of NAD(P)H-Dependent Hydride Transfer: The Properties of the Difluoromethylene Group, A Carbonyl Mimic
  Leriche, Caroline; He, Xuemei; Chang, Cheng-wei T.; Liu, Hung-wen
  Journal of the American Chemical Society (2003), 125 (21), 6348-6349CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The hallmarks of pyridine nucleotide-dependent dehydrogenase reactions are the stereo- and regiospecific hydride transfer between the nicotinamide coenzyme and the corresponding substrate. When the hydride is delivered from NAD(P)H to reduce the keto-substrate, the site of attack is always at the carbonyl carbon. However, the apparent regioselectivity of the hydride transfer is reversed when difluoromethylene is used as a carbonyl mimic in the NADH-dependent enzyme, TDP-L-rhamnose synthase, which catalyzes the conversion of TDP-6-deoxy-L-lyxo-4-hexulose to TDP-L-rhamnose. The obsd. reversed regioselectivity can be explained by two mechanisms. One involves the formation of a carbene intermediate followed by a rearrangement involving 1,2-H shift. This mechanistic proposal is theor. sound and would represent a rare example implicating the intermediacy of a carbene species in an enzyme reaction. However, our results are also consistent with a second mechanism in which the hydride addn. to the difluoromethylene moiety occurs at the difluorinated end, opposite from the site predicted on the basis of the redn. of a normal keto functional group. Such a regioselectivity is well precedented in chem. models because nucleophilic addn. to fluoroalkenes prefers a route in which the no. of fluorines β to the electron-rich carbon in the transition state is maximized. In this mechanism, the difluoromethylene group may be regarded as a carbonyl mimic with reversed polarity in enzyme catalysis. While further expts. are needed to discriminate between these mechanistic possibilities, the results reported here suggest that the apparent regioselectivity of hydride transfer in a pyridine nucleotide-dependent enzyme can be changed by altering the electrochem. properties of the reaction center.
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153. 153
  Bickelhaupt, F. M.; Hermann, H. L.; Boche, G. α-Stabilization of carbanions: fluorine is more effective than the heavier halogens. Angew. Chem., Int. Ed. 2006, 45, 823– 826, DOI: 10.1002/anie.200501633
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  (a) Bégué, J.-P.; Bonnet-Delpon, D. Fluoroartemisinins: metabolically more stable antimalarial artemisinin derivatives. ChemMedChem 2007, 2, 608– 624, DOI: 10.1002/cmdc.200600156
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  Fluoroartemisinins: metabolically more stable antimalarial artemisinin derivatives
  Begue, Jean-Pierre; Bonnet-Delpon, Daniele
  ChemMedChem (2007), 2 (5), 608-624CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This report is an overview on the design, prepn., and evaluation of metabolically stable artemisinins, using fluorine substitution. The chem. challenges encountered for the incorporation of fluorine-contg. elements and the prepn. of a large range of 10-trifluoromethyl artemisinin derivs. are detailed. Impact of the fluorine substitution on the antimalarial activity is also highlighted. Preclin. data of lead compds., and evidence for their strong and prolonged antimalarial activity are presented.
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  (b) Magueur, G.; Crousse, B.; Ourévitch, M.; Bonnet-Delpon, D.; Bégué, J.-P. Fluoro-artemisinins: when a gem-difluoroethylene replaces a carbonyl group. J. Fluorine Chem. 2006, 127, 637– 642, DOI: 10.1016/j.jfluchem.2005.12.013
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  154b
  Fluoro-artemisinins: When a gem-difluoroethylene replaces a carbonyl group
  Magueur, Guillaume; Crousse, Benoit; Ourevitch, Michele; Bonnet-Delpon, Daniele; Begue, Jean-Pierre
  Journal of Fluorine Chemistry (2006), 127 (4-5), 637-642CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
  Exo-gem-difluoromethylene-artemisinin (I) has been designed to mimic artemisinin. The classical Wittig olefination reaction applied to artemisinin failed. An alternative reaction involving the generation of an α-CF3 carbanion, from the corresponding bromide, allowed the access to the target compd. I, and could also be applied to the sugar series. The replacement of the carbonyl function by a difluoroethylene moiety resulted in a better antimalarial activity.
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155. 155
  (a) Tu, Y. Artemisinin- a gift from traditional Chinese medicine to the world (Nobel lecture). Angew. Chem., Int. Ed. 2016, 55, 10210– 10226, DOI: 10.1002/anie.201601967
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  (b) Ashley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, C.; Runcharoen, R.; Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan, R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.; Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi, P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.; Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.; Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.; Tracking Resistance to Artemisinin Collaboration Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 2014, 371, 411– 423, DOI: 10.1056/NEJMoa1314981
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  155b
  Spread of artemisinin resistance in Plasmodium falciparum malaria
  Ashley, E. A.; Dhorda, M.; Fairhurst, R. M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J. M.; Mao, S.; Sam, B.; Sopha, C.; Chuor, C. M.; Nguon, C.; Sovannaroth, S.; Pukrittayakamee, S.; Jittamala, P.; Chotivanich, K.; Chutasmit, K.; Suchatsoonthorn, C.; Runcharoen, R.; Hien, T. T.; Thuy-Nhien, N. T.; Thanh, N. V.; Phu, N. H.; Htut, Y.; Han, K.-T.; Aye, K. H.; Mokuolu, O. A.; Olaosebikan, R. R.; Folaranmi, O. O.; Mayxay, M.; Khanthavong, M.; Hongvanthong, B.; Newton, P. N.; Onyamboko, M. A.; Fanello, C. I.; Tshefu, A. K.; Mishra, N.; Valecha, N.; Phyo, A. P.; Nosten, F.; Yi, P.; Tripura, R.; Borrmann, S.; Bashraheil, M.; Peshu, J.; Faiz, M. A.; Ghose, A.; Hossain, M. A.; Samad, R.; Rahman, M. R.; Hasan, M. M.; Islam, A.; Miotto, O.; Amato, R.; MacInnis, B.; Stalker, J.; Kwiatkowski, D. P.; Bozdech, Z.; Jeeyapant, A.; Cheah, P. Y.; Sakulthaew, T.; Chalk, J.; Intharabut, B.; Silamut, K.; Lee, S. J.; Vihokhern, B.; Kunasol, C.; Imwong, M.; Tarning, J.; Taylor, W. J.; Yeung, S.; Woodrow, C. J.; Flegg, J. A.; Das, D.; Smith, J.; Venkatesan, M.; Plowe, C. V.; Stepniewska, K.; Guerin, P. J.; Dondorp, A. M.; Day, N. P.; White, N. J.
  New England Journal of Medicine (2014), 371 (5), 411-423, 13 pp.CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
  Background: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geog. extent of resistance is essential for planning containment and elimination strategies. Methods: Between May 2011 and Apr. 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kg of body wt. per day or 4 mg per kg, for 3 days, followed by a std. 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 h, and the parasite clearance half-lives were detd. Results: The median parasite clearance half-lives ranged from 1.9 h in the Democratic Republic of Congo to 7.0 h at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 h), strongly assocd. with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from Southern Vietnam to central Myanmar. The incidence of pre-treatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In Western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was assocd. with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. Conclusions: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is assocd. with mutations in kelch13. Prolonged courses of artemisinin- based combination therapies are currently efficacious in areas where std. 3-day treatments are failing. (Funded by the U.K. Department of International Development and others).
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156. 156
  (a) Dubowchik, G. M.; Vrudhula, V. M.; Dasgupta, B.; Ditta, J.; Chen, T.; Sheriff, S.; Sipman, K.; Witmer, M.; Tredup, J.; Vyas, D. M.; Verdoorn, T. A.; Bollini, S.; Vinitsky, A. 2-Aryl-2,2-difluoroacetamide FKBP12 ligands: synthesis and X-ray structural studies. Org. Lett. 2001, 3, 3987– 3990, DOI: 10.1021/ol0166909
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  156a
  2-Aryl-2,2-difluoroacetamide FKBP12 Ligands: Synthesis and X-ray Structural Studies
  Dubowchik, Gene M.; Vrudhula, Vivekananda M.; Dasgupta, Bireshwar; Ditta, Jonathan; Chen, Ti; Sheriff, Steven; Sipman, Karin; Witmer, Mark; Tredup, Jeffrey; Vyas, Dolatrai M.; Verdoorn, Todd A.; Bollini, Sagarika; Vinitsky, Alexander
  Organic Letters (2001), 3 (25), 3987-3990CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  2-Aryl-2,2-difluoroacetamido derivs. of proline and pipecolate esters I (X = F2, O, H2; Y = N, CH) and II (p = 1, 2; n = 2, 3; m = 0-3) are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 Ph ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.
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  (b) Bollini, S.; Herbst, J. J.; Gaughan, G. T.; Verdoorn, T. A.; Ditta, J.; Dubowchik, G. M.; Vinitsky, A. High-throughput fluorescence polarization method for identification of FKBP12 ligands. J. Biomol. Screening 2002, 7, 526– 530, DOI: 10.1177/1087057102238626
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  156b
  High-throughput fluorescence polarization method for identification of FKBP12 ligands
  Bollini, S.; Herbst, J. J.; Gaughan, G. T.; Verdoorn, T. A.; Ditta, J.; Dubowchik, G. M.; Vinitsky, A.
  Journal of Biomolecular Screening (2002), 7 (6), 526-530CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)
  FKBP12 is best known as the target of the widely used immunosuppressive drug FK506 but may also play a role in neuronal survival. Nonimmunosuppressive ligands of FKBP12 have been shown to have neuroprotective and neuroregenerative activity both in vitro and in vivo, stimulating interest in the development of high-throughput screens to rapidly identify novel ligands. FKBP12 was expressed as a His6-fusion in bacteria and purified by metal ion affinity and gel filtration chromatog. A high-throughput fluorescence polarization assay was developed to identify novel ligands of FKBP12. Dissocn. const. values of known FKBP12 ligands measured by the new method agreed closely with Ki values obtained by assaying inhibition of the rotamase activity of the enzyme. The fluorescence polarization assay is rapid, robust, and inexpensive and does not generate radioactive waste. It is very well suited for high-throughput screening efforts.
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157. 157
  Ye, X. M.; Konradi, A. W.; Smith, J.; Aubele, D. L.; Garofalo, A. W.; Marugg, J.; Neitzel, M. L.; Semko, C. M.; Sham, H. L.; Sun, M.; Truong, A. P.; Wu, J.; Zhang, H.; Goldbach, E.; Sauer, J.-M.; Brigham, E. F.; Bova, M.; Basi, G. S. Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II). Bioorg. Med. Chem. Lett. 2010, 20, 3502– 3506, DOI: 10.1016/j.bmcl.2010.04.148
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  Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II)
  Ye, Xiaocong M.; Konradi, Andrei W.; Smith, Jenifer; Aubele, Danielle L.; Garofalo, Albert W.; Marugg, Jennifer; Neitzel, Marty L.; Semko, Chris M.; Sham, Hing L.; Sun, Minghua; Truong, Anh P.; Wu, Jing; Zhang, Hongbin; Goldbach, Erich; Sauer, John-Michael; Brigham, Elizabeth F.; Bova, Michael; Basi, Guriqbal S.
  Bioorganic & Medicinal Chemistry Letters (2010), 20 (12), 3502-3506CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
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158. 158
  Xiamuxi, H.; Wang, Z.; Li, J.; Wang, Y.; Wu, C.; Yang, F.; Jiang, X.; Liu, Y.; Zhao, Q.; Chen, W.; Zhang, J.; Xie, Y.; Hu, T.; Xu, M.; Guo, S.; Akber Aisa, H.; He, Y.; Shen, J. Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multi-receptor atypical antipsychotics. Bioorg. Med. Chem. 2017, 25, 4904– 4916, DOI: 10.1016/j.bmc.2017.07.040
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  (a) Zanda, M. Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New J. Chem. 2004, 28, 1401– 1411, DOI: 10.1039/b405955g
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  Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification
  Zanda, Matteo
  New Journal of Chemistry (2004), 28 (12), 1401-1411CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
  A review. Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in the solid phase, for many different fluoroalkyl peptidomimetics, i.e., bis-trifluoromethyl (Tfm) analogs of Pepstatin A, which are nanomolar and selective inhibitors of the protozoal aspartyl protease Plasmepsin II; Tfm-malic peptidomimetics that are micromolar inhibitors of some matrix metalloproteinases; partially modified retro (PMR) and retro-inverso (PMRI) ψ[CH(CF3)NH] peptides with a strong proclivity to assume turn-like conformations; ψ[CH(CF3)NH] peptide mimics having a great potential as hybrids between natural peptides and hydrolytic transition state analogs; PMR peptides incorporating a trifluoroalanine surrogate. These novel classes of fluorinated peptide mimics are likely to represent just the tip of an iceberg formed by new peptidomimetic structures with unique biomedicinal and pharmaceutical properties.
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  (b) Sani, M.; Volonterio, A.; Zanda, M. The trifluoroethylamine function as peptide bond replacement. ChemMedChem 2007, 2, 1693– 1700, DOI: 10.1002/cmdc.200700156
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  The trifluoroethylamine function as peptide bond replacement
  Sani, Monica; Volonterio, Alessandro; Zanda, Matteo
  ChemMedChem (2007), 2 (12), 1693-1700CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Synthesis of peptidomimetics contg. a stereogenic trifluoroethylamine group in place of the peptide bond is discussed. Peptidomimetics contg. the trifluoroethylamine group in place of amide group have been found to be highly potent and metabolically stable inhibitors of cathepsin K.
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  (c) Brusoe, A. T.; Hartwig, J. F. Palladium-catalyzed arylation of fluoroalkylamines. J. Am. Chem. Soc. 2015, 137, 8460– 8468, DOI: 10.1021/jacs.5b02512
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  159c
  Palladium-Catalyzed Arylation of Fluoroalkylamines
  Brusoe, Andrew T.; Hartwig, John F.
  Journal of the American Chemical Society (2015), 137 (26), 8460-8468CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  We report the synthesis of fluorinated anilines by palladium-catalyzed coupling of fluoroalkylamines with aryl bromides and aryl chlorides. The products of these reactions are valuable because anilines typically require the presence of an electron-withdrawing substituent on nitrogen to suppress aerobic or metabolic oxidn., and the fluoroalkyl groups have steric properties and polarity distinct from those of more common electron-withdrawing amide and sulfonamide units. The fluoroalkylaniline products are unstable under typical conditions for C-N coupling reactions (heat and strong base). However, the reactions conducted with the weaker base KOPh, which has rarely been used in cross-coupling to form C-N bonds, occurred in high yields in the presence of a catalyst derived from com. available AdBippyPhos and [Pd(allyl)Cl]2. Under these conditions, the reactions occur with low catalyst loadings (<0.50 mol % for most substrates) and tolerate the presence of various functional groups that react with the strong bases that are typically used in Pd-catalyzed C-N cross-coupling reactions of aryl halides. The resting state of the catalyst is the phenoxide complex, [BippyPhosPd(Ar)OPh]; due to the electron-withdrawing property of the fluoroalkyl substituent, the turnover-limiting step of the reaction is reductive elimination to form the C-N bond.
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160. 160
  (a) Volonterio, A.; Bellosta, S.; Bravin, F.; Bellucci, M. C.; Bruche, L.; Colombo, G.; Malpezzi, L.; Mazzini, S.; Meille, S. V.; Meli, M.; Ramirez de Arellano, C.; Zanda, M. Synthesis, structure and conformation of partially-modified retro- and retro-inverso Ψ[NHCH(CF₃)]Gly peptides. Chem. - Eur. J. 2003, 9, 4510– 4522, DOI: 10.1002/chem.200304881
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  160a
  Synthesis, structure and conformation of partially-modified retro- and retro-inverso ψ[NHCH(CF3)]Gly peptides
  Volonterio, Alessandro; Bellosta, Stefano; Bravin, Fabio; Bellucci, Maria Cristina; Bruche, Luca; Colombo, Giorgio; Malpezzi, Luciana; Mazzini, Stefania; Meille, Stefano V.; Meli, Massimiliano; Ramirez de Arellano, Carmen; Zanda, Matteo
  Chemistry - A European Journal (2003), 9 (18), 4510-4522CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Partially modified retro- (PMR) and retro-inverso (PMRI) ψ[NHCH(CF3)]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure α-amino esters and peptides with enantiomerically and geometrically pure N-(4,4,4-trifluorocrotonoyl)oxazolidin-2-ones. The factors underlying the obsd. moderate to good diastereocontrol have been investigated. The conformations of model PMR-ψ[NHCH(CF3)]Gly tripeptides have been studied in soln. by 1H NMR spectroscopy supported by MD calcns., as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: (1) severe torsional restrictions about sp3 bonds in the [CO-CH2-CH(CF3)-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF3 group and the R side chain and (2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl3 soln. and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramol. hydrogen bonding. The relative configuration of the -C*H(CF3)NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochem. X-ray diffraction and ab initio computational studies showed that the [-CH(CF3)NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analog, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF3)-NH-CH backbone angle close to 120°, C-CF3 bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O-)NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron d. on the CF3 group, tetrahedral backbone carbon).
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  (b) Molteni, M.; Pesenti, C.; Sani, M.; Volonterio, A.; Zanda, M. Fluorinated peptidomimetics: synthesis, conformational and biological features. J. Fluorine Chem. 2004, 125, 1735– 1743, DOI: 10.1016/j.jfluchem.2004.09.014
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  160b
  Fluorinated peptidomimetics: synthesis, conformational and biological features
  Molteni, Marco; Pesenti, Cristina; Sani, Monica; Volonterio, Alessandro; Zanda, Matteo
  Journal of Fluorine Chemistry (2004), 125 (11), 1735-1743CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
  Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Our interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in solid phase, for many different fluoroalkyl peptidomimetics, some of which are overviewed in this paper: (a) ψ[CH(CF3)NH]-peptide mimics holding a great potential as hybrids between natural peptides and hydrolytic transition state analogs, (b) trifluoromethyl (Tfm) malic peptidomimetics as micromolar inhibitors of some matrix metalloproteinases, and (c) bis-Tfm analogs of pepstatin A, that are nanomolar and selective inhibitors of the protozoal aspartyl protease plasmepsin II.
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  (c) Molteni, M.; Bellucci, M. C.; Bigotti, S.; Mazzini, S.; Volonterio, A.; Zanda, M. Ψ[CH(CF₃)NH]Gly-peptides: synthesis and conformation analysis. Org. Biomol. Chem. 2009, 7, 2286– 2296, DOI: 10.1039/b901718f
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  160c
  Ψ[CH(CF3)NH]Gly-peptides: synthesis and conformation analysis
  Molteni, Marco; Bellucci, Maria Cristina; Bigotti, Serena; Mazzini, Stefania; Volonterio, Alessandro; Zanda, Matteo
  Organic & Biomolecular Chemistry (2009), 7 (11), 2286-2296CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  Ψ[CH(CF3)NH]Gly peptides, a conceptually new class of peptidomimetics having a stereogenic trifluoroethylamine group as a natural peptide-bond surrogate, have been synthesized by aza-Michael stereoselective addn. of α-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. Long range nuclear Overhauser effects, detected via ROESY expts., provided evidence that model Ψ[CH(CF3)NH]Gly-tetrapeptides incorporating a trifluoroethylamine mimic of the dipeptide loop Pro-Gly can be represented by an ensemble of unfolded and folded conformations. The latter are driven by the formation of a hydrogen bond between a carbonyl group and the aminic proton of the trifluoroethylamine unit. MD calcns. indicate a population of conformers which adopt folded β turn structures for all the L-peptides; on the other hand, a D-stereochem. at the Pro residue induces a natural folding towards a β hairpin conformation driven by the formation of a second hydrogen bond, regardless of the stereochem. of the stereogenic peptide bond surrogate.
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161. 161
  (a) Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J.-P.; Leger, S.; Li, C. S.; Massé, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005, 15, 4741– 4744, DOI: 10.1016/j.bmcl.2005.07.071
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  161a
  Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K
  Black, W. Cameron; Bayly, Christopher I.; Davis, Dana E.; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Leger, Serge; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Palmer, James T.; Percival, M. David; Robichaud, Joel; Tsou, Nancy; Zamboni, Robert
  Bioorganic & Medicinal Chemistry Letters (2005), 15 (21), 4741-4744CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The nonbasic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compds. are 10- to 20-fold more potent than the corresponding amide derivs. Compd. (I) is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.
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  .
  (b) Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.-P.; Gauthier, J. Y.; Kimmel, D. B.; Léger, S.; Massé, F.; McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Thérien, M.; Truong, V.-L.; Wesolowski, G.; Zamboni, R.; Black, W. C. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 2006, 16, 1985– 1989, DOI: 10.1016/j.bmcl.2005.12.071
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  161b
  Identification of a potent and selective non-basic cathepsin K inhibitor
  Li, Chun Sing; Deschenes, Denis; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Gauthier, Jacques Yves; Kimmel, Donald. B.; Leger, Serge; Masse, Frederic; McGrath, Mary E.; McKay, Daniel J.; Percival, M. David; Riendeau, Denis; Rodan, Sevgi B.; Therien, Michel; Truong, Vouy-Linh; Wesolowski, Gregg; Zamboni, Robert; Black, W. Cameron
  Bioorganic & Medicinal Chemistry Letters (2006), 16 (7), 1985-1989CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of L-873724 (I) as a potent and selective non-basic cathepsin K inhibitor. This compd. showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The vols. of distribution close to unity were consistent with this compd. not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.
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  (c) Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L.T.; Falgueyret, J.-P.; Kimmel, D. B.; Lamontagne, S.; Leger, S.; LeRiche, T.; Li, C. S.; Massé, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.; Truong, V.-L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18, 923– 928, DOI: 10.1016/j.bmcl.2007.12.047
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  The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
  Gauthier, Jacques Yves; Chauret, Nathalie; Cromlish, Wanda; Desmarais, Sylvie; Duong, Le T.; Falgueyret, Jean-Pierre; Kimmel, Donald B.; Lamontagne, Sonia; Leger, Serge; LeRiche, Tammy; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Nicoll-Griffith, Deborah A.; Oballa, Renata M.; Palmer, James T.; Percival, M. David; Riendeau, Denis; Robichaud, Joel; Rodan, Gideon A.; Rodan, Sevgi B.; Seto, Carmai; Therien, Michel; Truong, Vouy-Linh; Venuti, Michael C.; Wesolowski, Gregg; Young, Robert N.; Zamboni, Robert; Black, W. Cameron
  Bioorganic & Medicinal Chemistry Letters (2008), 18 (3), 923-928CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
  Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclin. species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
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  Merck & Co. drops osteoporosis drug odanacatib
  Mullard, Asher
  Nature Reviews Drug Discovery (2016), 15 (10), 669CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
  A discussion of the osteoporosis drug odanacatib.
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162. 162
  Isabel, E.; Mellon, C.; Boyd, M. J.; Chauret, N.; Deschênes, D.; Desmarais, S.; Falgueyret, J. P.; Gauthier, J. Y.; Khougaz, K.; Lau, C. K.; Léger, S.; Levorse, D. A.; Li, C. S.; Massé, F.; Percival, M. D.; Roy, B.; Scheigetz, J.; Thérien, M.; Truong, V. L.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. Difluoroethylamines as an amide isostere in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2011, 21, 920– 923, DOI: 10.1016/j.bmcl.2010.12.070
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  Butler, C. R.; Ogilvie, K.; Martinez-Alsina, L.; Barreiro, G.; Beck, E. M.; Nolan, C. E.; Atchison, K.; Benvenuti, E.; Buzon, L.; Doran, S.; Gonzales, C.; Helal, C. J.; Hou, X.; Hsu, M.-H.; Johnson, E. F.; Lapham, K.; Lanyon, L.; Parris, K.; O’Neill, B. T.; Riddell, D.; Robshaw, A.; Vajdos, F.; Brodney, M. A. Aminomethyl-derived beta secretase (BACE-1) inhibitors: engaging Gly230 without an anilide functionality. J. Med. Chem. 2017, 60, 386– 402, DOI: 10.1021/acs.jmedchem.6b01451
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164. 164
  (a) Chen, G.; Ren, H.; Turpoff, A.; Arefolov, A.; Wilde, R.; Takasugi, J.; Khan, A.; Almstead, N.; Gu, Z.; Komatsu, T.; Freund, C.; Breslin, J.; Colacino, J.; Hedrick, J.; Weetall, M.; Karp, G. M. Discovery of N-(4′-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication. Bioorg. Med. Chem. Lett. 2013, 23, 3942– 3946, DOI: 10.1016/j.bmcl.2013.04.050
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  (b) Zhang, X.; Zhang, N.; Chen, G.; Turpoff, A.; Ren, H.; Takasugi, J.; Morrill, C.; Zhu, J.; Li, C.; Lennox, W.; Paget, S.; Liu, Y.; Almstead, N.; Njoroge, F. G.; Gu, Z.; Komatsu, T.; Clausen, V.; Espiritu, C.; Graci, J.; Colacino, J.; Lahser, F.; Risher, N.; Weetall, M.; Nomeir, A.; Karp, G. M. Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B. Bioorg. Med. Chem. Lett. 2013, 23, 3947– 3953, DOI: 10.1016/j.bmcl.2013.04.049
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  Discovery of novel HCV inhibitors: Synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B
  Zhang, Xiaoyan; Zhang, Nanjing; Chen, Guangming; Turpoff, Anthony; Ren, Hongyu; Takasugi, James; Morrill, Christie; Zhu, Jin; Li, Chunshi; Lennox, William; Paget, Steven; Liu, Yalei; Almstead, Neil; George Njoroge, F.; Gu, Zhengxian; Komatsu, Takashi; Clausen, Valerie; Espiritu, Christine; Graci, Jason; Colacino, Joseph; Lahser, Fred; Risher, Nicole; Weetall, Marla; Nomeir, Amin; Karp, Gary M.
  Bioorganic & Medicinal Chemistry Letters (2013), 23 (13), 3947-3953CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides I [R1 = CHF2O, c-Pr; R2 = i-Pr, H, CH(CH2F)2, etc.] was prepd. and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compds. with low nanomolar potency against the HCV genotype 1b replicon. Among these, compd. I [R1 = CHF2O; R2 = CH(CH2F)2] was identified as a potent HCV replicon inhibitor (EC50 = 4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compd. I [R1 = CHF2O; R2 = CH(CH2F)2] had a good pharmacokinetic profile in rats with an IV half-life of 6 h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compds. These compds. hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.
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  (c) Zhang, N.; Zhang, X.; Zhu, J.; Turpoff, A.; Chen, G.; Morrill, C.; Huang, S.; Lennox, W.; Kakarla, R.; Liu, R.; Li, C.; Ren, H.; Almstead, N.; Venkatraman, S.; Njoroge, F. G.; Gu, Z.; Clausen, V.; Graci, J.; Jung, S. P.; Zheng, Y.; Colacino, J. M.; Lahser, F.; Sheedy, J.; Mollin, A.; Weetall, M.; Nomeir, A.; Karp, G.M. Structure–activity relationship (SAR) optimization of 6-(indol-2-yl)pyridine-3-sulfonamides: identification of potent, selective, and orally bioavailable small molecules targeting hepatitis C (HCV) NS4B. J. Med. Chem. 2014, 57, 2121– 2135, DOI: 10.1021/jm401621g
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  Fernandez, M. C.; Gonzalez-Garcia, M. R.; Liu, B.; Pfeifer, L. A. Phenyl Methanesulfonamide Derivatives Useful as MGAT-2 Inhibitors. World Patent Application WO-2013/112323 A1, Aug. 1, 2013.
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  Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Hiner, R. N.; Dorsey, G. F.; Noe, R. A.; Unwalla, R. J.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; van Arnold, J.; Bickett, D. M.; Moss, M. L.; Tian, G.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Croom, D. K. Structure-activity relationships for inhibition of type 1 and 2 human 5α-reductase and human adrenal 3β-hydroxy-Δ⁵-steroid dehydrogenase/3-keto-Δ⁵-steroid isomerase by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent. J. Med. Chem. 1995, 38, 2621– 2627, DOI: 10.1021/jm00014a015
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  (a) di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A. Novel aromatase and 5α-reductase inhibitors. J. Steroid Biochem. Mol. Biol. 1994, 49, 289– 294, DOI: 10.1016/0960-0760(94)90270-4
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  Novel aromatase and 5α-reductase inhibitors
  Di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A.
  Journal of Steroid Biochemistry and Molecular Biology (1994), 49 (4-6), 289-94CODEN: JSBBEZ; ISSN:0960-0760.
  Inhibitors of aromatase and 5α-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, resp. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compd. was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compd. was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17β-amidic side chains, three compds., namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5α-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, resp. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compds. were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, resp.
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  .
  (b) Giudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Ihelè, C.; Nesi, M.; Panzeri, A.; di Salle, E. FCE 28260, a new 5α-reductase inhibitor: in vitro and in vivo effects. J. Steroid Biochem. Mol. Biol. 1996, 58, 299– 305, DOI: 10.1016/0960-0760(96)00040-4
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  167b
  FCE 28260, a new 5α-reductase inhibitor: in vitro and in vivo effects
  Giudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Iehle, C.; Nesi, M.; Panzeri, A.; di Salle, E.
  Journal of Steroid Biochemistry and Molecular Biology (1996), 58 (3), 299-305CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier)
  FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compd. causes inhibition of rat and human prostatic enzymes, with IC50 values of 15 an d16 nM, resp., compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5αR type 2 and 1 isoenzymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isoenzymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult rats, FCE 28260 reduced prostatic DHT concns. 6 h after oral dosing with a potency similar to that of finasteride (65% redn. at 1 mg/kg) but was found to be markedly more potent than the ref. compd. at 24 h (74% redn. in prostate DHT at 10 mg/kg, compared to 26% redn. induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.
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  .
  (c) di Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Délos, S.; Martin, P. M. PNU 157706, a novel dual type I and II 5α-reductase inhibitor. J. Steroid Biochem. Mol. Biol. 1998, 64, 179– 186, DOI: 10.1016/S0960-0760(97)00158-1
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  167c
  PNU 157706, a novel dual type I and II 5α-reductase inhibitor
  Di Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Delos, S.; Martin, P. M.
  Journal of Steroid Biochemistry and Molecular Biology (1998), 64 (3-4), 179-186CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Science Ltd.)
  PNU 157706 is a novel dual inhibitor of 5α-reductase (5α-R), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). Tested on a crude prepn. of human or rat prostatic 5α-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, resp., compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5α-R type I and II isoenzymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), particularly on the type I isoenzyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting redn. of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, resp.). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate wt. in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate wt., the ED50 values being 0.12 and 1.9 mg/kg/day, resp. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5α-R with a very marked antiprostatic effect in the rat.
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  (d) Basileo, G.; Breda, M.; James, C. A. Determination of PNU-157706, a new dual inhibitor of 5α-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detection. J. Chromatogr., Biomed. Appl. 1998, 719, 191– 197, DOI: 10.1016/S0378-4347(98)00412-5
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  167d
  Determination of PNU 157706, a new dual inhibitor of 5α-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detection
  Basileo, G.; Breda, M.; James, C. A.
  Journal of Chromatography B: Biomedical Sciences and Applications (1998), 719 (1 + 2), 191-197CODEN: JCBBEP; ISSN:0378-4347. (Elsevier Science B.V.)
  A HPLC procedure was developed and validated for detg. nanogram per mL concns. of the dual 5a-reductase inhibitor PNU 157706 in rat plasma. The compd. was extd. from plasma with di-Et ether followed by purifn. on a CN cartridge. The chromatog. sepn. was performed on a C18 column with water-acetonitrile-methanol mixt. as eluent. UV detection at 210 nm was used for the quantification of the compd. over the concn. range 5-500 ng/mL plasma. The method has a lower limit of quantification of 5 ng/mL and good precision and accuracy. This method performed well during anal. of several toxicokinetic and pharmacokinetic studies in the rat.
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168. 168
  (a) Drury, J. E.; Di Costanzo, L.; Penning, T. M.; Christianson, D. W. Inhibition of human steroid 5α-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex. J. Biol. Chem. 2009, 284, 19786– 19790, DOI: 10.1074/jbc.C109.016931
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  (b) Karnsomwan, W.; Rungrotmongkol, T.; De-Eknamkul, W.; Chamni, S. chamni, S. In silico prediction of human steroid 5α-reductase type II. Med. Chem. Res. 2016, 25, 1049– 1056, DOI: 10.1007/s00044-016-1541-y
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  In silico structural prediction of human steroid 5α-reductase type II
  Karnsomwan, Wiranpat; Rungrotmongkol, Thanyada; De-Eknamkul, Wanchai; Chamni, Supakarn
  Medicinal Chemistry Research (2016), 25 (6), 1049-1056CODEN: MCREEB; ISSN:1054-2523. (Springer)
  Steroid 5α-reductase type II is a membrane-assocd. enzyme in an oxidoreductase family. This enzyme, which is found in male sexual organs, plays the important biol. actions toward steroid metab. Overexpression of 5α-reductase type II has affected the balance between testosterone and dihydrotestosterone, which implicates the androgenic disorders, including prostate cancer, hirsutism, and androgenic alopecia. Lack of single-crystal X-ray structures of 5α-reductase has hindered mechanistic understanding and delayed the discovery and development of an effective inhibitor. Herein, we illustrated a comparative structure of 5α-reductase type II that derived from the homol. modeling, employing a membrane-bound protein, isoprenylcysteine carboxyl methyltransferase as a homologous template. A catalytic pocket and the transmembrane site were identified. The resulting in silico structure was validated via Ramachandran plot and confirmed by docking studies of 30 known 5α-reductase type I and type II inhibitors, including finasteride and dutasteride. The comparative docking study of the derived in silico 5α-reductase type II and 5β-reductase, a reported surrogate enzyme, was conducted. Our homol. model approx. fitted to the membrane-assocd. character and showed the reasonable docking results, which depicted the well-defined comparative three-dimensional structure applicable for steroid reductase drug design.
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169. 169
  (a) Howbert, J. J.; Grossman, C. S.; Crowell, T. A.; Rieder, B. J.; Harper, R. W.; Kramer, K. E.; Tao, E. V.; Aikins, J.; Poore, G. A. Novel agents effective against solid tumors: the diarylsulfonylureas. Synthesis, activities, and analysis of quantitative structure-activity relationships. J. Med. Chem. 1990, 33, 2393– 2407, DOI: 10.1021/jm00171a013
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170. 170
  (a) Houghton, P. J.; Houghton, J. A. Antitumor diarylsulfonylureas: novel agents with unfulfilled promise. Invest. New Drugs 1996, 14, 271– 280, DOI: 10.1007/BF00194530
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  (b) Owa, T.; Nagasu, T. Novel sulphonamide derivatives for the treatment of cancer. Expert Opin. Ther. Pat. 2000, 10, 1725– 1740, DOI: 10.1517/13543776.10.11.1725
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  Novel sulphonamide derivatives for the treatment of cancer
  Owa, Takashi; Nagasu, Takeshi
  Expert Opinion on Therapeutic Patents (2000), 10 (11), 1725-1740CODEN: EOTPEG; ISSN:1354-3776. (Ashley Publications Ltd.)
  A review with 265 refs. is given. The sulfonamides constitute an important class of therapeutic agents in current medicinal science. After the discovery by Gerhard Domagk, of sulphamidochrysoidine (prontosil) as the first antibiotic sulfa-drug an active metabolite of the drug, sulphanilamide, was further derivatized in order to find compds. exhibiting superior antibacterial activity or different pharmacol. effects. Diversification of the sulphanilamide structure led to the serial development of improved antibiotics, insulin-releasing hypoglycemic drugs, carbonic anhydrase- (CA) inhibitory diuretics, anti-hypertensive drugs etc. It is of particular interest that various structurally novel sulfonamide derivs. have recently been reported to show substantial anti-tumor activity in vitro and/or in vivo. Although they have a common chem. motif of an arom./heterocyclic sulfonamide, there are a variety of mechanisms for their anti-tumor action, such as disruption of microtubule assembly, cell cycle arrest in the G1 phase, functional suppression of the transcriptional activator NF-Y, angiogenesis inhibition and carbonic anhydrase inhibition. Furthermore, some of these compds. selected via elaborate preclin. screenings are currently being evaluated in clin. trials. This review summarizes recent patents and related papers which have disclosed novel classes of sulfonamide derivs. for the treatment of cancer.
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171. 171
  Forouzesh, B.; Takimoto, C. H.; Goetz, A.; Diab, S.; Hammond, L. A.; Smetzer, L.; Schwartz, G.; Gazak, R.; Callaghan, J. T.; Von Hoff, D. D.; Rowinsky, E. K. A Phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies. Clin. Cancer Res. 2003, 9, 5540– 5549
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  A Phase I and pharmacokinetic study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies
  Forouzesh, Bahram; Takimoto, Chris H.; Goetz, Andrew; Diab, Sami; Hammond, Lisa A.; Smetzer, Leslie; Schwartz, Garry; Gazak, Robert; Callaghan, John T.; Von Hoff, Daniel D.; Rowinsky, Eric K.
  Clinical Cancer Research (2003), 9 (15), 5540-5549CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
  This study was conducted to assess the feasibility of administering the oral diarylsulfonylurea (DSU) ILX-295501 on a weekly for 3 wk every 4-wk schedule. The study also sought to det. the max. tolerated dose (MTD) of ILX-295501 on this schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. The initial starting dose of ILX-295501 was 100 mg/m2, which was equiv. to one-sixth of the highest dose that did not induce irreversible toxicity in dogs, and, using a modified Fibonnaci search scheme to guide dose level selection, the following dose levels were evaluated: 100, 200, 400, 600, 900, 1350, and 1800 mg/m2. Because severe toxicities were being reported in other trials at doses that encompassed this range and a cumulative toxicity profile was emerging, the study was suspended and then reinitiated to further reevaluate the lower dosing range. In the second part of the study, the following dose levels were selected a priori for evaluation: 400, 800, 1000, 1250, and 1500 mg/m2; and a modified continual reassessment model was used for dose assignment to det. the MTD, which was defined a priori as the highest dose in which the incidence of dose-limiting toxicity in the first course did not exceed 20%. Forty-nine patients were treated with 142 courses of ILX-295501 at doses ranging from 100 to 1800 mg/m2. The incidences of dose-limiting toxicity, principally neutropenia and thrombocytopenia, were unacceptably high at ILX-295501 doses exceeding 1000 mg/m2, which was detd. to be the MTD for both minimally pretreated and heavily pretreated (HP) patients. In contrast to the first generation of DSUs, particularly sulofenur, clin. relevant levels of oxidized Hb (metHb) and secondary hemolytic anemia, were not noted. One HP patient with non-small cell lung carcinoma experienced a partial response. Pharmacokinetic studies revealed that ILX-295501 was absorbed slowly, with peak plasma concns. (Cmax) achieving 6.02 h, on av., after oral administration. The pharmacokinetic behavior of ILX-295501 was characterized by dose proportionality, a relatively small apparent vol. of distribution at steady state (Vss/F), averaging 8.02 ± 14.08 L, and low apparent total body clearance (CLt/F) rate (mean, 0.036 ± 0.116 L/h). The initial drug distribution phase was rapid [harmonic mean half-life (t1/2α), 2.1±7.0 min], whereas the terminal elimination phase was slow (harmonic mean t1/2β, 150.6 ± 80.2 h). The recommended dose for Phase II studies of the oral DSU ILX-295501 administered weekly for 3 wk every 4 wk is 1000 mg/m2/day for both minimally pretreated and HP patients. The characteristics of the myelosuppressive effects of ILX-295501, the paucity of severe nonhematol. toxicities, and preliminary antitumor activity warrant disease-directed evaluations of ILX-295501.
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172. 172
  (a) Toth, J. E.; Grindey, G. B.; Ehlhardt, W. J.; Ray, J. E.; Boder, G. B.; Bewley, J. R.; Klingerman, K. K.; Gates, S. B.; Rinzel, S. M.; Schultz, R. M.; Weir, L. C.; Worzalla, J. F. Sulfonimidamide analogs of oncolytic sulfonylureas. J. Med. Chem. 1997, 40, 1018– 1025, DOI: 10.1021/jm960673l
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  Sulfonimidamide Analogs of Oncolytic Sulfonylureas
  Toth, John E.; Grindey, Gerald B.; Ehlhardt, William J.; Ray, James E.; Boder, George B.; Bewley, Jesse R.; Klingerman, Kim K.; Gates, Susan B.; Rinzel, Sharon M.; Schultz, Richard M.; Weir, Leonard C.; Worzalla, John F.
  Journal of Medicinal Chemistry (1997), 40 (6), 1018-1025CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A series of sulfonimidamide analogs of the oncolytic diarylsulfonylureas was synthesized and evaluated for in vitro cytotoxicity against CEM cells, in vivo antitumor activity against subaxillary implanted 6C3HED lymphosarcoma, and metabolic breakdown to the o-sulfate of p-chloroaniline. The sepd. enantiomers of 1 sulfonimidamide analog displayed very different activities in the in vivo screening model. In general, several analogs demonstrated excellent growth inhibitory activity in the 6C3HED model when dosed orally or i.p. A correlative structure-activity relationship to the oncolytic sulfonylureas was not apparent.
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  (a) Luzina, E. L.; Popov, A. V. Synthesis and anticancer activity of N-bis(trifluoromethyl)alkyl-N′-thiazolyl and N-bis(trifluoromethyl)alkyl-N′-benzothiazolyl ureas. Eur. J. Med. Chem. 2009, 44, 4944– 4953, DOI: 10.1016/j.ejmech.2009.08.007
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  Métayer, B.; Compain, G.; Jouvin, K.; Martin-Mingot, A.; Bachmann, C.; Marrot, J.; Evano, G.; Thibaudeau, S. Chemo- and stereo-selective synthesis of fluorinated enamides from ynamides in HF/pyridine: second-generation approach to potent ureas bioisosteres. J. Org. Chem. 2015, 80, 3397– 3410, DOI: 10.1021/jo502699y
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  (a) Mewshaw, R. E.; Marquis, K. L.; Shi, X.; McGaughey, G.; Stack, G.; Webb, M. B.; Abou-Gharbia, M.; Wasik, T.; Scerni, R.; Spangler, T.; Brennan, J. A.; Mazandarani, H.; Coupet, J.; Andree, T. H. New generation dopaminergic agents 4. Exploiting the 2-methyl chroman scaffold. Synthesis and evaluation of two novel series of 2-(aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano [2,3-e]indole and indol-8-one derivatives. Tetrahedron 1998, 54, 7081– 7108, DOI: 10.1016/S0040-4020(98)00349-4
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  New generation dopaminergic agents. 5. heterocyclic bioisosteres that exploit the 3-OH-N'-phenylpiperazine dopaminergic template
  Mewshaw, Richard E.; Verwijs, Antoine; Shi, Xiaojie; Mcgaughey, Georgia B.; Nelson, James A.; Mazandarani, Hossein; Brennan, Julie A.; Marquis, Karen L.; Coupet, Joseph; Andree, Terrance H.
  Bioorganic & Medicinal Chemistry Letters (1998), 8 (19), 2675-2680CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
  The synthesis of several bioisosteric analogs based on the 3-OH-N'-phenylpiperazine dopamine D2 agonist template is described. The indolone (I) and 2-CF3-benzimidazole (II) were obsd. to have excellent affinity for the D2 receptor. Several D4 selective compds. were also identified. Mol. modeling studies and a putative bioactive conformation are discussed.
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  Banks, J. W.; Batsanov, A. S.; Howard, J. A. K.; O’Hagan, D.; Rzepa, H. S.; Martin-Santamaria, S. The preferred conformation of α-fluoroamides. J. Chem. Soc., Perkin Trans. 2 1999, 2409– 2411, DOI: 10.1039/a907452j
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  The preferred conformation of α-fluoroamides
  Banks, John W.; Batsanov, Andrei S.; Howard, Judith A. K.; O'Hagan, David; Rzepa, Henry S.; Martin-Santamaria, Sonsoles
  Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1999), (11), 2409-2411CODEN: JCPKBH; ISSN:0300-9580. (Royal Society of Chemistry)
  X-Ray structures of two α-fluoroamide derivs. show the O:C-C-F moiety tending towards a trans planar conformation, for which ab initio calcns. suggest a deep (up to 8 kcal mol-1) potential min.
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177. 177
  Olivato, P. R.; Guerrero, S. A.; Yreijo, M. H.; Rittner, R.; Tormena, C. F. Conformational and electronic interaction studies of 2-fluoro-substituted N,N-dimethylamides. J. Mol. Struct. 2002, 607, 87– 99, DOI: 10.1016/S0022-2860(01)00761-X
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  Briggs, C. R. S.; O’Hagan, D.; Howard, J. A. K.; Yufit, D. S. The C-F bond as a tool in the conformational control of amides. J. Fluorine Chem. 2003, 119, 9– 13, DOI: 10.1016/S0022-1139(02)00243-9
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  The C-F bond as a tool in the conformational control of amides
  Briggs, Caroline R. S.; O'Hagan, David; Howard, Judith A. K.; Yufit, Dmitrii S.
  Journal of Fluorine Chemistry (2003), 119 (1), 9-13CODEN: JFLCAR; ISSN:0022-1139. (Elsevier Science B.V.)
  The conformation of 2-fluoro-N-(2-fluoroethyl)-propionamide 4 in the solid state indicates the influence of both a β-F-amide gauche effect and an α-fluoroamide effect. The structure reveals the influence of two recently obsd. stereoelectronic effects assoc. with the C-F bond, which resulted in the successful prediction of the solid state conformation of amide 4. A gauche relation (-69.9°) was obsd. for atoms N(1)-C(4)-C(5)-F and a syn planar (2.0°) relation was obsd. for N(1)-C(3)-C(2)-F. The paper demonstrates the predictive power of using the C-F bond as a tool in influencing the conformation of amides and peptides.
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179. 179
  Winkler, M.; Moraux, T.; Khairy, H. A.; Scott, R. H.; Slawin, A. M. Z.; O’Hagan, D. Synthesis and vanilloid receptor (TRPV1) activity of the enantiomers of α-fluorinated capsaicin. ChemBioChem 2009, 10, 823– 828, DOI: 10.1002/cbic.200800709
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  (a) Jones, C. R.; Baruah, P. K.; Thompson, A. L.; Scheiner, S.; Smith, M. D. Can. a C–H···O interaction be a determinant of conformation?. J. Am. Chem. Soc. 2012, 134, 12064– 12071, DOI: 10.1021/ja301318a
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  (b) Driver, R. W.; Claridge, T. D. W.; Scheiner, S.; Smith, M. D. Torsional and electronic factors control the C–H···O interaction. Chem. - Eur. J. 2016, 22, 16513– 16521, DOI: 10.1002/chem.201602905
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  Torsional and Electronic Factors Control the C-H...O Interaction
  Driver, Russell W.; Claridge, Timothy D. W.; Scheiner, Steve; Smith, Martin D.
  Chemistry - A European Journal (2016), 22 (46), 16513-16521CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The precise role of nonconventional hydrogen bonds such as the C-H...O interaction in influencing the conformation of small mols. remains unresolved. Here the authors survey β-turn mimetics using x-ray crystallog. and NMR spectroscopy in conjunction with quantum calcn., and conclude that favorable torsional and electronic effects are important for the population of states with conformationally influential C-H...O interactions. Results also highlight the challenge in attempting to deconvolute a myriad of interdependent noncovalent interactions to focus on the contribution of a single one. Within a small mol. that is designed to resemble the complexity of the environment within peptides and proteins, the interplay of different steric burdens, hydrogen-acceptor/-donor properties and rotational profiles illustrate why unambiguous conclusions based solely on NMR chem. shift data are extremely challenging to rationalize.
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  (c) Koeller, S.; Thomas, C.; Peruch, F.; Deffieux, A.; Massip, S.; Léger, J.-M.; Desvergne, J.-P.; Milet, A.; Bibal, B. α-Halogenoacetanilides as hydrogen-bonding organocatalysts that activate carbonyl bonds: fluorine versus chlorine and bromine. Chem. - Eur. J. 2014, 20, 2849– 2859, DOI: 10.1002/chem.201303662
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  α-Halogenoacetanilides as Hydrogen-Bonding Organocatalysts that Activate Carbonyl Bonds: Fluorine versus Chlorine and Bromine
  Koeller, Sylvain; Thomas, Coralie; Peruch, Frederic; Deffieux, Alain; Massip, Stephane; Leger, Jean-Michel; Desvergne, Jean-Pierre; Milet, Anne; Bibal, Brigitte
  Chemistry - A European Journal (2014), 20 (10), 2849-2859CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  α-Halogenoacetanilides (X = F, Cl, Br) with substituents on the Ph ring were examd. as H-bonding organocatalysts designed for the double activation of C=O bonds through NH and CH donor groups. Depending on the halide substituents, the double H-bond involved a nonconventional C···H···O interaction with either a H-CXn (n= 1-2, X = Cl, Br) or a H-CAr bond (X = F), as shown in the solid-state crystal structures and by mol. modeling. In addn., the catalytic properties of α-haloacetanilides were evaluated in the ring-opening polymn. of lactide, in the presence of a tertiary amine as cocatalyst. The α-dichloro- and α-dibromoacetanilides contg. electron-deficient arom. groups afforded the most attractive double H-bonding properties towards C=O bonds, with a N-H···O···H···CX2 interaction.
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  (d) Jaun, B.; Seebach, D.; Mathad, R. I. Note: Helix or no helix of β-peptides containing β³hAla(αF) residues?. Helv. Chim. Acta 2011, 94, 355– 361, DOI: 10.1002/hlca.201100023
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  (e) Chekhlov, A. N.; Aksinenko, A. Yu.; Pushin, A. N.; Sokolov, V. B. An unusually strong intramolecular C-H•••N hydrogen bond in 3-(α-hydroperfluoroisobutyryl)-2-[(α-hydroperfluoroisobutyryl)imino]-1,3-thiazolidine. Russ. Chem. Bull. 1995, 44, 1531– 1532, DOI: 10.1007/BF00714447
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  (f) Chekhlov, A. N. Crystal and molecular structure of 3-(α-hydroperfluoroisobutyryl)-2-[(α-hydroperfluoroisobutyryl)imino]-1,3-thiazolidine with an unusually short intramolecular C-H•••N hydrogen bond. Kristallografiya 1995, 842– 847
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  Crystal and molecular structure of 3-(α-hydroperfluoroisobutyryl)-2-(α-hydroperfluoroisobutyryl)imino-1,3-thiazolidine with an unusually short intramolecular C-H···N hydrogen bond
  Chekhlov, A. N.
  Kristallografiya (1995), 40 (5), 842-7CODEN: KRISAJ; ISSN:0023-4761. (MAIK Nauka)
  The title compd. is monoclinic, space group P21/n, with a 9.203(1), b 10.349(1), c 17.299(2) Å, and β 95.74(1)°; Z = 4, dc = 1.857; R = 0.059 for 2075 reflections. At. coordinates are given. The 5-membered thiazolidine ring has half-chair conformation. This mol. has an unusually short H bond C-H...N with H...N distance 2.00(3) Å. The mol. also has a significantly shortened contact S...O 2.652(2) Å, with nonvalent interaction between S and O atoms. In the crystal structure, the mols. are connected in centrosym. dimer pairs with intermol. H bonds of C-H...O type with H...O distance of 2.38(3) Å.
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  (g) Brewitz, L.; Arteaga Arteaga, F.; Yin, L.; Alagiri, K.; Kumagai, N.; Shibasaki, M. Direct catalytic asymmetric Mannich-type reaction of α- and β-fluorinated amides. J. Am. Chem. Soc. 2015, 137, 15929– 15939, DOI: 10.1021/jacs.5b11064
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  180g
  Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated Amides
  Brewitz, Lennart; Arteaga, Fernando Arteaga; Yin, Liang; Alagiri, Kaliyamoorthy; Kumagai, Naoya; Shibasaki, Masakatsu
  Journal of the American Chemical Society (2015), 137 (50), 15929-15939CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amts. of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivs. for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-contg. small mols., α- and β-fluorinated carbonyl compds. have been neglected in direct enolization chem. because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Bronsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chem.
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  (h) Brewitz, L.; Noda, H.; Kumagai, N.; Shibasaki, M. Structural and computational investigation of intramolecular N•••H interactions in α- and β-fluorinated 7-azaindoline amides. Eur. J. Org. Chem. 2017, DOI: 10.1002/ejoc.201701083
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  Jones, C. R.; Dan Pantos, G. D.; Morrison, A. J.; Smith, M. D. Plagiarizing proteins: enhancing efficiency in asymmetric hydrogen-bonding catalysis through positive cooperativity. Angew. Chem., Int. Ed. 2009, 48, 7391– 7394, DOI: 10.1002/anie.200903063
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  Plagiarizing Proteins: Enhancing Efficiency in Asymmetric Hydrogen-Bonding Catalysis through Positive Cooperativity
  Jones, Christopher R.; Dan Pantos, G.; Morrison, Angus J.; Smith, Martin D.
  Angewandte Chemie, International Edition (2009), 48 (40), 7391-7394, S7391/1-S7391/127CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A hairpin turn intramol. H-bonded thiourea-urea catalyst was proficient in the highly enantioselective Mukaiyama-Mannich reaction of arom. BOC-aldimines with silyl ketene acetal nucleophile, providing β-aryl β-amino acids in 97 to >99% ee. Deletion of the urea H-bond donor group revealed that the effect of conformational ordering on the asym. induction is significant but relatively small. The intramol. H-bonded catalyst out-competed the urea-deleted catalyst in a competition reaction, suggesting tighter ligand-receptor binding in the transition state and tighter noncovalent interactions in the former case, and also exhibited higher anion-binding ability - consistent with cooperative ligand binding.
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182. 182
  Unione, L.; Alcalá, M.; Echeverria, B.; Serna, S.; Ardá, A.; Franconetti, A.; Cañada, F. J.; Diercks, T.; Reichardt, N.; Jiménez-Barbero, J. Fluoroacetamide moieties as NMR spectroscopy probes for the molecular recognition of GlcNAc-containing sugars: modulation of the CH−π stacking interactions by different fluorination patterns. Chem. - Eur. J. 2017, 23, 3957– 3965, DOI: 10.1002/chem.201605573
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  Fluoroacetamide Moieties as NMR Spectroscopy Probes for the Molecular Recognition of GlcNAc-Containing Sugars: Modulation of the CH-π Stacking Interactions by Different Fluorination Patterns
  Unione, Luca; Alcala, Maria; Echeverria, Begona; Serna, Sonia; Arda, Ana; Franconetti, Antonio; Canada, F. Javier; Diercks, Tammo; Reichardt, Niels; Jimenez-Barbero, Jesus
  Chemistry - A European Journal (2017), 23 (16), 3957-3965CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  We herein propose the use of fluoroacetamide and difluoroacetamide moieties as sensitive tags for the detection of sugar-protein interactions by simple 1H and/or 19F NMR spectroscopy methods. In this process, we have chosen the binding of N,N'-diacetyl chitobiose, a ubiquitous disaccharide fragment in glycoproteins, by wheat-germ agglutinin (WGA), a model lectin. By using satn.-transfer difference (STD)-NMR spectroscopy, we exptl. demonstrate that, under soln. conditions, the mol. that contained the CHF2CONH- moiety is the stronger arom. binder, followed by the analog with the CH2FCONH- group and the natural mol. (with the CH3CONH- fragment). In contrast, the mol. with the CF3CONH- isoster displayed the weakest intermol. interaction (one order of magnitude weaker). Because sugar-arom. CH-π interactions are at the origin of these observations, these results further contribute to the characterization and exploration of these forces and offer an opportunity to use them to unravel complex recognition processes.
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183. 183
  (a) Depreux, P.; Lesieur, D.; Mansour, H. A.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola, B.; Yous, S.; Demarque, A.; Adam, G.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J. Med. Chem. 1994, 37, 3231– 3239, DOI: 10.1021/jm00046a006
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  183a
  Synthesis and Structure-Activity Relationships of Novel Naphthalenic and Bioisosteric Related Amidic Derivatives as Melatonin Receptor Ligands
  Depreux, Patrick; Lesieur, Daniel; Mansour, Hamid Ait; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; et al.
  Journal of Medicinal Chemistry (1994), 37 (20), 3231-9CODEN: JMCMAR; ISSN:0022-2623.
  A series of N-naphthylethyl amide derivs. were synthesized and evaluated as melatonin receptor ligands. The affinity of each compd. for the melatonin receptor was detd. by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent on the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analog was a poor ligand. N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, a selective ligand of the melatonin receptor and an agonist deriv., has been selected for clin. development.
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  (b) Leclerc, V.; Fourmaintraux, E.; Depreux, P.; Lesieur, D.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola-Lemaître, B.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Bioorg. Med. Chem. 1998, 6, 1875– 1887, DOI: 10.1016/S0968-0896(98)00147-3
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  Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands
  Leclerc, Veronique; Fourmaintraux, Eric; Depreux, Patrick; Lesieur, Daniel; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; Guardiola-Lemaitre, Beatrice; Andrieux, Jean
  Bioorganic & Medicinal Chemistry (1998), 6 (10), 1875-1887CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)
  A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogs of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n-Pr urea deriv. is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This mol., a Pr deriv., or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclin. development.
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  (c) Ettaoussi, M.; Sabaouni, A.; Rami, M.; Boutin, J. A.; Delagrange, P.; Renard, P.; Spedding, M.; Caignard, D.-H.; Berthelot, P.; Yous, S. Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT₁/MT₂) and serotoninergic 5-HT_2C dual ligands (I). Eur. J. Med. Chem. 2012, 49, 310– 323, DOI: 10.1016/j.ejmech.2012.01.027
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  Qiu, X.-L.; Xu, X.-H.; Qing, F.-L. Recent advances in the synthesis of fluorinated nucleosides. Tetrahedron 2010, 66, 789– 843, DOI: 10.1016/j.tet.2009.11.001
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  Noble, S.; Goa, K. L. Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs 1997, 54, 447– 472, DOI: 10.2165/00003495-199754030-00009
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  Gemcitabine. A review of its pharmacology and clinical potential in non-small-cell lung cancer and pancreatic cancer
  Noble, Stuart; Goa, Karen L.
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  A review with 119 refs. Gemcitabine is a deoxycytidine analog which was originally investigated for its antiviral effects but has since been developed as an anticancer therapy. Gemcitabine monotherapy produced an objective tumor response in 18-26% of patients with advanced non-small-cell lung cancer (NSCLC) and appears to have efficacy similar to that of cisplatin plus etoposide. Objective response rates ranging 26-54% were recorded when gemcitabine was combined with cisplatin, and 1-yr survival duration after such treatment ranged 35-61%. Improvements in a range of NSCLC disease symptoms and/or in general performance status occurred in many patients who received gemcitabine, with or without cisplatin, in 3 clin. trials. Gemcitabine appears to be cost effective compared with best supportive care for NSCLC. In addn., direct costs assocd. with administration of gemcitabine monotherapy may be lower than those for some other NSCLC chemotherapy options. The combination of gemcitabine plus cisplatin was assocd. with a lower cost-per-tumor response than cisplatin plus etoposide or cisplatin plus vinorelbine, according to a retrospective cost-effectiveness anal. In a single comparative study in patients with advanced pancreatic cancer, gemcitabine was more effective than fluorouracil with respect to survival duration and general clin. status. It also showed modest antitumor and palliative efficacy in patients refractory to fluorouracil. Gemcitabine appears to be well tolerated, although further comparisons with other chemotherapy regimens are required. The data indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide in patients with NSCLC. Data from noncomparative studies suggest that the combination of gemcitabine and cisplatin has an acceptable tolerability profile. In a single trial in patients with pancreatic cancer, fluorouracil was better tolerated than gemcitabine; however, gemcitabine was generally well tolerated overall in this study. Thus, gemcitabine (with or without cisplatin) may prove attractive to patients with advanced NSCLC, given their limited life expectancy and the toxicity assocd. with many other chemotherapy regimens. Gemcitabine is a valuable new chemotherapy option for patients with advanced pancreatic cancer, a disease considered incurable at present. Its apparent survival and palliative benefits over fluorouracil require confirmation, but are encouraging, as the need to improve both the duration and quality of survival in these patients is well recognized.
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  Hui, C. K.; Lau, G.K. K. Clevudine for the treatment of chronic hepatitis B virus infection. Expert Opin. Invest. Drugs 2005, 14, 1277– 1284, DOI: 10.1517/13543784.14.10.1277
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  (a) Sofia, M. J.; Bao, S.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.-R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A. M.; Micolochick Steur, H. M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-D-2′deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis c virus. J. Med. Chem. 2010, 53, 7202– 7218, DOI: 10.1021/jm100863x
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  (b) Appleby, T. C.; Perry, J. K.; Murakami, E.; Barauskas, O.; Feng, J.; Cho, A.; Fox, D., III; Wetmore, D. R.; McGrath, M. E.; Ray, A. S.; Sofia, M. J.; Swaminathan, S.; Edwards, T. E. Structural basis for RNA replication by the hepatitis C virus polymerase. Science 2015, 347, 771– 775, DOI: 10.1126/science.1259210
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  Structural basis for RNA replication by the hepatitis C virus polymerase
  Appleby, Todd C.; Perry, Jason K.; Murakami, Eisuke; Barauskas, Ona; Feng, Joy; Cho, Aesop; Fox, David, III; Wetmore, Diana R.; McGrath, Mary E.; Ray, Adrian S.; Sofia, Michael J.; Swaminathan, S.; Edwards, Thomas E.
  Science (Washington, DC, United States) (2015), 347 (6223), 771-775CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Nucleotide analog inhibitors have shown clin. success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by detg. crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our anal. revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A β loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clin. active metabolite formed by sofosbuvir, to elucidate key mol. interactions in the active site.
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  Van Roey, P.; Salerno, J. M.; Chu, C.-K.; Schinazi, R. F. Correlation between preferred sugar ring conformation and activity of nucleoside analogues against human immunodeficiency virus. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 3929– 3933, DOI: 10.1073/pnas.86.11.3929
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  Gore, K. R.; Harikrishna, S.; Pradeepkumar, P. I. Influence of 2′-fluoro versus 2′-O-methyl substituent on the sugar puckering of 4′-C-aminomethyluridine. J. Org. Chem. 2013, 78, 9956– 9962, DOI: 10.1021/jo4012333
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  Zeng, D.; Zhang, R.; Nie, Q.; Cao, L.; Shang, L.; Yin, Z. Discovery of 2′-α-C-methyl-2′-β-C-fluorouridine phosphoramidate prodrugs as inhibitors of hepatitis C virus. ACS Med. Chem. Lett. 2016, 7, 1197– 1201, DOI: 10.1021/acsmedchemlett.6b00270
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  Pallan, P. S.; Prakash, T. P.; de Leon, A. R.; Egli, M. Limits of RNA 2′-OH mimicry by fluorine: crystal structure of bacillus halodurans RNase H bound to a 2′-FRNA:DNA hybrid. Biochemistry 2016, 55, 5321– 5325, DOI: 10.1021/acs.biochem.6b00849
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  Limits of RNA 2'-OH mimicry by fluorine: Crystal structure of Bacillus halodurans RNase H bound to a 2'-FRNA:DNA hybrid
  Pallan, Pradeep S.; Prakash, Thazha P.; de Leon, Arnie R.; Egli, Martin
  Biochemistry (2016), 55 (38), 5321-5325CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  RNase H1 cleaves the RNA strand of RNA:DNA hybrids. Replacement of RNA 2'-OH groups by F (FRNA) is commonly used to stabilize aptamers and siRNAs. However, FRNA:DNA hybrids fail to elicit RNase H1 activity. The underlying reasons are unclear, as 2'-OH groups are not directly involved in cleavage. Here, the authors detd. the crystal structure of Bacillus halodurans RNase H1 bound to a FRNA:DNA hybrid. The structure pointed to dynamic (slippage of the FRNA:DNA hybrid relative to the enzyme), geometric (different curvatures of FRNA:DNA and RNA:DNA hybrids), and electronic reasons (Mg2+ absent from the active site of the FRNA:DNA complex) for the loss of RNase H1 activity.
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192. 192
  (a) Hinderaker, M. P.; Raines, R. T. An electronic effect on protein structure. Protein Sci. 2003, 12, 1188– 1194, DOI: 10.1110/ps.0241903
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  192a
  An electronic effect on protein structure
  Hinderaker, Matthew P.; Raines, Ronald T.
  Protein Science (2003), 12 (6), 1188-1194CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)
  The well-known preference of the peptide bond for the trans conformation has been attributed to steric effects. Here, we show that a proline residue with an N-formyl group (Hi-1-C'i-1=Oi-1), in which Hi-1 presents less steric hindrance than does Oi-1, likewise prefers a trans conformation. Thus, the preference of the peptide bond for the trans conformation cannot be explained by steric effects alone. Rather, an n → π* interaction between the oxygen of the peptide bond (Oi-1), and the subsequent carbonyl carbon in the polypeptide chain (C'i) also contributes to this preference. The Oi-1 and C'i distance and Oi-1···C'i=Oi angle are esp. favorable for such an n → π* interaction in a polyproline II helix. We propose that this electronic effect provides substantial stabilization to this and other elements of protein structure.
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  .
  (b) Horng, J.-C.; Raines, R. T. Stereoelectronic effects on polyproline conformation. Protein Sci. 2006, 15, 74– 83, DOI: 10.1110/ps.051779806
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  192b
  Stereoelectronic effects on polyproline conformation
  Horng, Jia-Cherng; Raines, Ronald T.
  Protein Science (2006), 15 (1), 74-83CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)
  The polyproline type II (PPII) helix is a prevalent conformation in both folded and unfolded proteins, and is known to play important roles in a wide variety of biol. processes. Polyproline itself can also form a type I (PPI) helix, which has a disparate conformation. Here, we use derivs. of polyproline, (Pro)10, (Hyp)10, (Flp)10, and (flp)10, where Hyp is (2S,4R)-4-hydroxyproline, Flp is (2S,4R)-4-fluoroproline, and flp is (2S,4S)-4-fluoroproline, to probe for a stereoelectronic effect on the conformation of polyproline. CD spectral analyses show that 4R electron-withdrawing substituents stabilize a PPII helix relative to a PPI helix, even in a solvent that favors the PPI conformation, such as n-propanol. The stereochem. at C4 ordains the relative stability of PPI and PPII helixes, as (flp)10 forms a mixt. of PPI and PPII helixes in water and a PPI helix in n-propanol. The conformational preferences of (Pro)10 are intermediate between those of (Hyp)10/(Flp)10 and (flp)10. Interestingly, PPI helixes of (flp)10 exhibit cold denaturation in n-propanol with a value of Ts near 70°. Together, these data show that stereoelectronic effects can have a substantial impact on polyproline conformation and provide a rational means to stabilize a PPI or PPII helix.
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  .
  (c) Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.; Raines, R. T. Conformational stability of collagen relies on a stereoelectronic effect. J. Am. Chem. Soc. 2001, 123, 777– 778, DOI: 10.1021/ja005542v
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  192c
  Conformational Stability of Collagen Relies on a Stereoelectronic Effect
  Bretscher, Lynn E.; Jenkins, Cara L.; Taylor, Kimberly M.; DeRider, Michele L.; Raines, Ronald T.
  Journal of the American Chemical Society (2001), 123 (4), 777-778CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Here, we demonstrate for the first time that a stereoelectronic effect is crit. for the conformational stability of a protein.
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193. 193
  Bacqué, E. Influence of fluorination at position 16 of antibacterial pristinamycins II. Chimia 2004, 58, 128– 132, DOI: 10.2533/000942904777678109
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194. 194
  Erickson, J.; McLoughlin, J. I. Hydrogen bond donor properties of the difluoromethyl group. J. Org. Chem. 1995, 60, 1626– 1631, DOI: 10.1021/jo00111a021
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  194
  Hydrogen Bond Donor Properties of the Difluoromethyl Group
  Erickson, Jon A.; McLoughlin, Jim I.
  Journal of Organic Chemistry (1995), 60 (6), 1626-31CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A theor. and exptl. study of the existence and the properties of the difluoromethyl group acting as a hydrogen bond donor has been carried out. An intramol. CF2H...O:C interaction was examd. using semiempirical MO calcns. of both a non-hydrogen-bonded and hydrogen-bonded conformation of a CF2H-substituted pyrazolecarboxamide fungicide. Results revealed a short H...O contact, a significant energy stabilization, and a lowering in the IR spectrum of 22 cm-1. The exptl. IR spectrum of this mol. gave two carbonyl stretching frequencies, one lower by 18 cm-1, very similar to the calcd. no. Low-temp. NMR results are also consistent with a geometry having the possibility of an intramol. CF2H...O:C hydrogen bond. The hydrogen bond in this system may be related to the enhanced biol. activity of the CF2H compd. over its CF3 counterpart. In addn., ab initio MO methods were employed to examine inter- and intramol. hydrogen-bonding models of the difluoromethyl group. The results showed that the CF2H...O:C interaction has a binding energy of ∼1.0 kcal mol-1 and a H...O distance of ∼2.4 Å.
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195. 195
  (a) Walter, H.; Tobler, H.; Gribkov, D.; Corsi, D. Sedaxane, isopyrazam and solatenol: novel broad-spectrum fungicides inhibiting succinate dehydrogenase (SDH) - synthesis challenges and biological aspects. Chimia 2015, 69, 425– 434, DOI: 10.2533/chimia.2015.425
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  (b) Jeschke, P. Progress of modern agricultural chemistry and future prospects. Pest Manage. Sci. 2016, 72, 433– 455, DOI: 10.1002/ps.4190
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  Progress of modern agricultural chemistry and future prospects
  Jeschke, Peter
  Pest Management Science (2016), 72 (3), 433-455CODEN: PMSCFC; ISSN:1526-498X. (John Wiley & Sons Ltd.)
  Agriculture is facing an enormous challenge: it must ensure that enough high-quality food is available to meet the needs of a continually growing population. Current and future agronomic prodn. of food, feed, fuel and fiber requires innovative solns. for existing and future challenges, such as climate change, resistance to pests, increased regulatory demands, renewable raw materials or requirements resulting from food chain partnerships. Modern agricultural chem. has to support farmers to manage these tasks. Today, the so-called 'side effects' of agrochems. regarding yield and quality are gaining more importance. Agrochem. companies with a strong research and development focus will have the opportunity to shape the future of agriculture by delivering innovative integrated solns. This review gives a comprehensive overview of the innovative products launched over the past 10 years and describes the progress of modern agricultural chem. and its future prospects. © 2015 Society of Chem. Industry.
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196. 196
  Goldberg, K.; Groombridge, S.; Hudson, J.; Leach, A. G.; MacFaul, P. A.; Pickup, A.; Poultney, R.; Scott, J. S.; Svensson, P. H.; Sweeney, J. Oxadiazole isomers: all bioisosteres are not created equal. MedChemComm 2012, 3, 600– 604, DOI: 10.1039/c2md20054f
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  Oxadiazole isomers: all bioisosteres are not created equal
  Goldberg, Kristin; Groombridge, Sam; Hudson, Julian; Leach, Andrew G.; MacFaul, Philip A.; Pickup, Adrian; Poultney, Ruth; Scott, James S.; Svensson, Per H.; Sweeney, Joseph
  MedChemComm (2012), 3 (5), 600-604CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compds. were evaluated and found to have significant differences in their various phys. and pharmaceutical properties. Exptl. and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects.
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197. 197
  (a) Narjes, F.; Koehler, K. F.; Koch, U.; Gerlach, B.; Colarusso, S.; Steinkuhler, C.; Brunetti, M.; Altamura, S.; De Francesco, R.; Matassa, V. G. A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease. Bioorg. Med. Chem. Lett. 2002, 12, 701– 704, DOI: 10.1016/S0960-894X(01)00842-3
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  197a
  A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease
  Narjes, Frank; Koehler, Konrad F.; Koch, Uwe; Gerlach, Benjamin; Colarusso, Stefania; Steinkuhler, Christian; Brunetti, Mirko; Altamura, Sergio; De Francesco, Raffaele; Matassa, Victor G.
  Bioorganic & Medicinal Chemistry Letters (2002), 12 (4), 701-704CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
  The difluoromethyl group was designed by computational chem. methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor AcAspGlu-NHCH(CHPH2)CO-Glu-NHCH(CH2C6H11)CONHCH(CH2CHF2)R (I, R = CHO) Ki 30 nM and reversible covalent inhibitors (I, R = CO2H) Ki 0.5 nM; and (I, R = COCO2H) Ki* 10 pM.
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  (b) Di Marco, S.; Rizzi, M.; Volpari, C.; Walsh, M. A.; Narjes, F.; Colarusso, S.; De Francesco, R.; Matassa, V. G.; Sollazzo, M. J. Inhibition of the hepatitis C virus NS3/4A protease: the crystal structures of two protease-inhibitor complexes. J. Biol. Chem. 2000, 275, 7152– 7157, DOI: 10.1074/jbc.275.10.7152
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  (c) Ontoria, J. M.; Di Marco, S.; Conte, I.; Di Francesco, M. E.; Gardelli, C.; Koch, U.; Matassa, V. G.; Poma, M.; Steinkühler, C.; Volpari, C.; Harper, S. The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease. J. Med. Chem. 2004, 47, 6443– 6446, DOI: 10.1021/jm049435d
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198. 198
  (a) Desiraju, G. R. The C-H···O hydrogen bond: structural implications and supramolecular design. Acc. Chem. Res. 1996, 29, 441– 449, DOI: 10.1021/ar950135n
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  198a
  The C-H···O Hydrogen Bond: Structural Implications and Supramolecular Design
  Desiraju, Gautam R.
  Accounts of Chemical Research (1996), 29 (9), 441-449CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review with 64 refs.
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  .
  (b) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl bioisostere: examining the “lipophilic hydrogen bond donor” concept. J. Med. Chem. 2017, 60, 797– 804, DOI: 10.1021/acs.jmedchem.6b01691
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  198b
  Difluoromethyl Bioisostere: Examining the "Lipophilic Hydrogen Bond Donor" Concept
  Zafrani, Yossi; Yeffet, Dina; Sod-Moriah, Gali; Berliner, Anat; Amir, Dafna; Marciano, Daniele; Gershonov, Eytan; Saphier, Sigal
  Journal of Medicinal Chemistry (2017), 60 (2), 797-804CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  There is a growing interest in org. compds. contg. the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepd. and their drug-like properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were detd. using Abraham's solute 1H NMR anal. The difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the exptl. Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ consts. These results may aid in the rational design of drugs contg. the difluoromethyl moiety.
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  .
  (c) Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J. CF₂H, a hydrogen bond donor. J. Am. Chem. Soc. 2017, 139, 9325– 9332, DOI: 10.1021/jacs.7b04457
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  198c
  CF2H, a Hydrogen Bond Donor
  Sessler, Chanan D.; Rahm, Martin; Becker, Sabine; Goldberg, Jacob M.; Wang, Fang; Lippard, Stephen J.
  Journal of the American Chemical Society (2017), 139 (27), 9325-9332CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The CF2H group, a potential surrogate for the OH group, can act as an unusual hydrogen bond donor, as confirmed ty crystallog., spectroscopic, and computational methods. Here, we demonstrate the bioisosterism of the OH and CF2H groups and the important roles of CF2-H···O hydrogen bonds in influencing intermol. interactions and conformational preferences. Exptl. evidence, corroborated by theory, reveals the distinctive nature of CF2H hydrogen bonding interactions relative to their normal OH hydrogen bonding counterparts.
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199. 199
  Zheng, Z. B.; D’Andrea, S. V.; Sun, L.-Q.; Wang, A. X.; Chen, Y.; Bowsher, M.; Hiebert, S.; Friborg, J.; Falk, P.; Hernandez, D.; Yu, F.; Sheaffer, A. K.; Zhai, G.; Knipe, J. O.; Mosure, K.; Rajamani, R.; Ng, A.; Gao, Q.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Sulfonamide inhibitors of hepatitis C virus NS3 protease bearing a novel P1 cyclopropyl difluoromethyl moiety. ACS Med. Chem. Lett., 2018, DOI : DOI: 10.1021/acsmedchemlett.7b00503
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200. 200
  Lin, C.-W.; Dutta, S.; Asatryan, A.; Chiu, Y.-L.; Wang, H.; Clifton, J., II; Campbell, A.; Liu, W. Pharmacokinetics, safety, and tolerability of single and multiple doses of ABT-493: a first-in-human study. J. Pharm. Sci. 2017, 106, 645– 651, DOI: 10.1016/j.xphs.2016.10.007
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201. 201
  Rodriguez-Torres, M.; Glass, S.; Hill, J.; Freilich, B.; Hassman, D.; Di Bisceglie, A. M.; Taylor, J. G.; Kirby, B. J.; Dvory-Sobol, H.; Yang, J. C.; An, D.; Stamm, L. M.; Brainard, D. M.; Kim, S.; Krefetz, D.; Smith, W.; Marbury, T.; Lawitz, E. GS-9857 in patients with chronic hepatitis C virus genotype 1–4 infection: a randomized, double-blind, dose-ranging phase 1 study. J. Viral Hepatitis 2016, 23, 614– 622, DOI: 10.1111/jvh.12527
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  GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study
  Rodriguez-Torres, M.; Glass, S.; Hill, J.; Freilich, B.; Hassman, D.; Di Bisceglie, A. M.; Taylor, J. G.; Kirby, B. J.; Dvory-Sobol, H.; Yang, J. C.; An, D.; Stamm, L. M.; Brainard, D. M.; Kim, S.; Krefetz, D.; Smith, W.; Marbury, T.; Lawitz, E.
  Journal of Viral Hepatitis (2016), 23 (8), 614-622CODEN: JVHEER; ISSN:1365-2893. (John Wiley & Sons Ltd.)
  Summary : GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-assocd. variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 lab. abnormalities were obsd. in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alk. phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median max. redns. in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was assocd. with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.
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202. 202
  (a) Xu, Y.; Prestwich, G. D. Concise synthesis of acyl migration-blocked 1,1-difluorinated analogues of lysophosphatidic acid. J. Org. Chem. 2002, 67, 7158– 7161, DOI: 10.1021/jo0203037
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  202a
  Concise Synthesis of Acyl Migration-Blocked 1,1-Difluorinated Analogs of Lysophosphatidic Acid
  Xu, Yong; Prestwich, Glenn D.
  Journal of Organic Chemistry (2002), 67 (20), 7158-7161CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) is an important phospholipid mediator produced by activated platelets and by ovarian cancer cells. Efforts to understand LPA signaling through G-protein-coupled receptors are hampered by the facile acyl migration that results in equilibration to a mixt. of the 1- or 2-acyl species under physiol. conditions. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogs from D-mannitol 1,2:5,6-bis-acetonide to give two 1,1-difluorodeoxy analogs of (2R)-acyl-sn-glycerol 3-phosphate. These compds. are migration-blocked analogs of the labile sn-2 LPA species. The 19F NMR of diastereotopic fluorines of the difluoromethyl group shows an unexpected solvent dependence.
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  .
  (b) Xu, Y.; Qian, L.; Pontsler, A. V.; McIntyre, T. M.; Prestwich, G. D. Synthesis of difluoromethyl substituted lysophosphatidic acid analogues. Tetrahedron 2004, 60, 43– 49, DOI: 10.1016/j.tet.2003.11.001
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  202b
  Synthesis of difluoromethyl substituted lysophosphatidic acid analogues
  Xu, Yong; Qian, Lian; Pontsler, Aaron V.; McIntyre, Thomas M.; Prestwich, Glenn D.
  Tetrahedron (2004), 60 (1), 43-49CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)
  Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biol. that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with nuclear hormone receptor PPARγ. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogs from (S)-1,2,4-butanetriol to give two 3-difluoromethyl substituted analogs of 2-acyl-sn-glycerol 3-phosphate. These compds. are migration-blocked analogs of the liable sn-2 LPA species. Preliminary studies were conducted on a nuclear reporter assay in which monocytic cells were transfected with a luciferase construct activated by a PPARγ nuclear receptor response element and have shown that the 3-difluoromethyl substituted analogs are fully active as natural LPA.
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203. 203
  (a) Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Suresh, M. R.; Knaus, E. E. Synthesis of celecoxib analogues possessing an N-difluoromethyl-1,2-dihydropyrid-2-one 5-lipoxygenase pharmacophore: biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. J. Med. Chem. 2009, 52, 1525– 1529, DOI: 10.1021/jm8015188
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  (b) Yu, G.; Praveen Rao, P. N.; Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Velázquez, C. A.; Suresh, M. R.; Knaus, E. E. Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual Inhibitors of cyclooxygenases and 5-lipoxygenase. Bioorg. Med. Chem. Lett. 2010, 20, 2168– 2173, DOI: 10.1016/j.bmcl.2010.02.040
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  203b
  Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual inhibitors of cyclooxygenases and 5-lipoxygenase
  Yu, Gang; Praveen Rao, P. N.; Chowdhury, Morshed A.; Abdellatif, Khaled R. A.; Dong, Ying; Das, Dipankar; Velazquez, Carlos A.; Suresh, Mavanur R.; Knaus, Edward E.
  Bioorganic & Medicinal Chemistry Letters (2010), 20 (7), 2168-2173CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  A new group of acetic acid and propionic acid regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compds. exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isoenzyme. Attachment of the N-difluoromethyl-1,2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, i.e., absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl)acetic acid (I) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Mol. modeling (docking) studies showed that the highly electroneg. CHF2 substituent present in I, that showed a modest selectivity for the COX-2 isoenzyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO2NH2) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region contg. the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5-LOX inhibitory drugs.
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204. 204
  Romanenko, V. D.; Kukhar, V. P. Fluorinated phosphonates: synthesis and biomedical application. Chem. Rev. 2006, 106, 3868– 3935, DOI: 10.1021/cr051000q
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  Fluorinated Phosphonates: Synthesis and Biomedical Application
  Romanenko, Vadim D.; Kukhar, Valery P.
  Chemical Reviews (Washington, DC, United States) (2006), 106 (9), 3868-3935CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. The synthesis, fundamental chem. properties, and biomedical uses of the phosphonic acid derivs. that bear at least one F substituent on the organyl moiety are the subject of this review, which is organized as follows. The 1st part is a survey of synthetic methods used for the prepn. of fluorinated phosphonates. The 2nd part consists of a presentation of the different types of fluorophosphonates having significant biol. importance. The 3rd part describes the use of fluorinated phosphonates in biomedical studies (e.g. enzyme inhibitors, catalytic antibodies, antiviral agents, antitumor agents, anti-platelet-aggregation agents). Discussion of basic aspects of phosphonate and organofluorine chem. is reduced to min. to avoid redundancy to the long series of papers already published in journals and books. Also no particular attention will be paid to subjects that have recently been reviewed. In such cases, only the most important trends are briefly summarized. Literature coverage for the review extends up to Apr. 2006.
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  (a) Blackburn, G. M.; Kent, D. E. A novel synthesis of R- and γ-fluoroalkylphosphonates. J. Chem. Soc., Chem. Commun. 1981, 511– 513, DOI: 10.1039/C39810000511
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  (a) Chambers, R. D.; O’Hagan, D.; Lamont, R. B.; Jaina, S. C. The difluoromethylenephosphonate moiety as a phosphate mimic: X-ray structure of 2-amino-1,1,-difluoroethylphosphonic acid. J. Chem. Soc., Chem. Commun. 1990, 1053– 1054, DOI: 10.1039/c39900001053
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  Some influences of fluorine in bioorganic chemistry
  O'Hagan, David; Rzepa, Henry S.
  Chemical Communications (Cambridge) (1997), (7), 645-652CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  A review with 76 refs. The stereochem. outcome on processing fluorinated substrate analogs by enzymes can often be controlled by electronic and stereoelectronic factors assocd. with the fluorine atoms. Interpreting or predicting the behavior of fluorinated compds. is complex and has led to the term flustrates (fluorine-contg. substrates) being coined. However, a greater appreciation of the electronic and stereoelectronic properties of org. fluorine renders the behavior of these compds. more interpretable.
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  Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T. New prospects toward the synthesis of difluoromethylated phosphate mimics. Chem. - Eur. J. 2016, 22, 10284– 10293, DOI: 10.1002/chem.201601310
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  New Prospects toward the Synthesis of Difluomethylated Phosphate Mimics
  Ivanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, Thomas
  Chemistry - A European Journal (2016), 22 (30), 10284-10293CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review of the prepn., reactions and biolical activities of difluoromethylated phosphonate-contg. mols. The difluoromethyl phosphonate motif plays a crucial role in the development of bioactive mols. as it is considered as a phosphate bioisoster. Since 2010, a renewal of interest to enlarge the panel of reactions to access these difluoromethylated phosphonate-contg. mols. was witnessed. This Concept article charts the recent progress that was made.
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  (a) Bialy, L.; Waldmann, H. Inhibitors of protein tyrosine phosphatases: next-generation drugs?. Angew. Chem., Int. Ed. 2005, 44, 3814– 3839, DOI: 10.1002/anie.200461517
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  Inhibitors of protein tyrosine phosphatases: Next-generation drugs?
  Bialy, Laurent; Waldmann, Herbert
  Angewandte Chemie, International Edition (2005), 44 (25), 3814-3839CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The protein tyrosine phosphatases (PTPs) constitute a family of closely related key regulatory enzymes that dephosphorylate phosphotyrosine residues in their protein substrates. Malfunctions in PTP activity are linked to various diseases, ranging from cancer to neurol. disorders and diabetes. Consequently, PTPs have emerged as promising targets for therapeutic intervention in recent years. In this review, general aspects of PTPs and the development of small-mol. inhibitors of PTPs by both academic research groups and pharmaceutical companies are discussed. Different strategies have been successfully applied to identify potent and selective inhibitors. These studies constitute the basis for the future development of PTP inhibitors as drugs.
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  Recent Advances in the Discovery of Competitive Protein Tyrosine Phosphatase 1B Inhibitors for the Treatment of Diabetes, Obesity, and Cancer
  Combs, Andrew P.
  Journal of Medicinal Chemistry (2010), 53 (6), 2333-2344CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review.
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209. 209
  (a) Smyth, M. S.; Ford, H., Jr.; Burke, T. R., Jr. A general method for the preparation of benzylic R,R-difluorophosphonic acids; nonhydrolyzable mimetics of phosphotyrosine. Tetrahedron Lett. 1992, 33, 4137– 4140, DOI: 10.1016/S0040-4039(00)74672-7
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  Copper-Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl Difluoromethylphosphonates: A General Approach to Fluorinated Phosphate Mimics
  Ivanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Poisson, Thomas; Pannecoucke, Xavier
  Angewandte Chemie, International Edition (2015), 54 (45), 13406-13410CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A general and efficient access to aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates is described. The developed methodol. using TMSCF2PO(OEt)2, iodonium salts and a Cu salt provided a straightforward manifold to reach these highly relevant products. The reaction proved to be highly functional group tolerant and proceeded under mild conditions, giving the corresponding products in good to excellent yields. This method represents the 1st general synthetic route to this important class of fluorinated scaffolds, which are well-recognized as in vivo stable phosphate surrogates.
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  (c) Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T. Copper-mediated introduction of the CF₂PO(OEt)₂ motif: scope and limitations. Chem. - Eur. J. 2017, 23, 17318– 17338, DOI: 10.1002/chem.201703542
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  Copper-Mediated Introduction of the CF2PO(OEt)2 Motif: Scope and Limitations
  Ivanova, Maria V.; Bayle, Alexandre; Besset, Tatiana; Pannecoucke, Xavier; Poisson, Thomas
  Chemistry - A European Journal (2017), 23 (68), 17318-17338CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Herein, a general procedure to access CF2PO(OEt)2-contg. mols. is reported. The reagent CuCF2PO(OEt)2 is accessible by a simple protocol and a broad range of substrates can be functionalized. The procedure allows the conversion of aryl diazonium salts, as well as aryl, heteroaryl, vinyl and alkynyl iodonium salts, into the corresponding fluorinated mols. at room temp. Mechanistic studies were performed to gain a better understanding of the reaction pathway. Under similar conditions, vinyl and aryl iodides, allyl halides, and benzyl bromides were also functionalized, and the scope and limitations of the reaction were studied. Finally, the procedure was extended to disulfides to offer new access to SCF2PO(OEt)2-contg. mols.
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  (a) Panigrahi, K.; Eggen, M.; Maeng, J.-H.; Shen, Q.; Berkowitz, D. B. The α,α-difluorinated phosphonate L-pSer-analogue: an accessible chemical tool for studying kinase-dependent signal transduction. Chem. Biol. 2009, 16, 928– 936, DOI: 10.1016/j.chembiol.2009.08.008
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  The α,α-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase- Dependent Signal Transduction
  Panigrahi, Kaushik; Eggen, MariJean; Maeng, Jun-Ho; Shen, Quanrong; Berkowitz, David B.
  Chemistry & Biology (Cambridge, MA, United States) (2009), 16 (9), 928-936CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
  A review. This overview focuses on the (α,α-difluoromethylene)phosphonate mimic of phosphoserine (pCF2Ser) and its application to the study of kinase-mediated signal transduction-pathways of great interest to drug development. The most versatile modes of access to these chem. biol. tools are discussed, organized by method of PCF2-C bond formation. The pCF2-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a "constitutive phosphorylation" phenotype and is seen to support native protein-protein interactions that depend on serine phosphorylation. Signal transduction pathways studied with this chem. biol. approach include the regulation of p53 tumor suppressor protein activity and of melatonin prodn. Given these successes, the future is bright for the use of such "teflon phospho-amino acid mimics" to map kinase-based signaling pathways.
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  (b) Arrendale, A.; Kim, K.; Choi, J. Y.; Li, W.; Geahlen, R. L.; Borch, R. F. Synthesis of a phosphoserine mimetic prodrug with potent 14–3-3 protein inhibitory activity. Chem. Biol. 2012, 19, 764– 771, DOI: 10.1016/j.chembiol.2012.05.011
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  Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity
  Arrendale, Allison; Kim, Keunho; Choi, Jun Young; Li, Wei; Geahlen, Robert L.; Borch, Richard F.
  Chemistry & Biology (Oxford, United Kingdom) (2012), 19 (6), 764-771CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)
  Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs contg. phosphorylated serine and threonine residues. To create small mols. that inhibit such interactions, we developed methodol. for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small mol. inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylenephosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concns. when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concn.-dependent manner that correlates well with its ability to inhibit cell growth. This methodol. can be applied to target a variety of proteins contg. phosphoserine and other phosphoamino acid binding domains.
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  (a) Rye, C. S.; Baell, J. B. Phosphate isosteres in medicinal chemistry. Curr. Med. Chem. 2005, 12, 3127– 3141, DOI: 10.2174/092986705774933452
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  Phosphate isosteres in medicinal chemistry
  Rye, C. S.; Baell, J. B.
  Current Medicinal Chemistry (2005), 12 (26), 3127-3141CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)
  A review. The phosphate group is at the heart of an enormous no. of biol. processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biol. activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognize the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chem. research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognizing domains such as Src homol. 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilization of the phosphate moiety as part of an inhibitor is severely limited by the enzymic lability and poor cellular bioavailability of this highly charged recognition element. The development of phosphate isosteres attempts to address these issues by introducing a non-scissile bond and utilizing groups with less charge that are still able to interact favorably with the target protein in much the same way as the phosphate group does. Many phosphate mimics retain the phosphorus atom such as in the highly successful fluoromethylene phosphonates, whereas others have lost the tetrahedral phosphate geometry and are based on the combination of one or more carboxylate groups that generally reduce the overall charge of the mol. This review focuses on the recent developments and the use of phosphate isosteres in medicinal chem., covering roughly the past four years.
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  (b) Elliott, T. S.; Slowey, A.; Ye, Y.; Conway, S. J. The use of phosphate bioisosteres in medicinal chemistry and chemical biology. MedChemComm 2012, 3, 735– 751, DOI: 10.1039/c2md20079a
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  The use of phosphate bioisosteres in medicinal chemistry and chemical biology
  Elliott, Thomas S.; Slowey, Aine; Ye, Yulin; Conway, Stuart J.
  MedChemComm (2012), 3 (7), 735-751CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
  A review. Phosphate and pyrophosphate groups play a central role in cellular signalling and consequently are of great interest to both medicinal chemists and chem. biologists. However, the design of mols. that can interfere with phosphate-based processes is recognized as a significant challenge, esp. when the resulting compds. must show good cellular penetration and stability. Herein, we have reviewed the full range of phosphate bioisosteres currently reported and provided the context of their deployment. We aim to provide a useful ref. for medicinal chemists and chem. biologists who are engaged in the design of mols. that target phosphate-binding proteins.
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  (c) Zhang, Y.; Borrel, A.; Ghemtio, L.; Regad, L.; Boije af Gennäs, G.; Camproux, A.-C.; Yli-Kauhaluoma, J.; Xhaard, H. Structural isosteres of phosphate groups in the protein data bank. J. Chem. Inf. Model. 2017, 57, 499– 516, DOI: 10.1021/acs.jcim.6b00519
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  Structural Isosteres of Phosphate Groups in the Protein Data Bank
  Zhang, Yuezhou; Borrel, Alexandre; Ghemtio, Leo; Regad, Leslie; Boije af Gennas, Gustav; Camproux, Anne-Claude; Yli-Kauhaluoma, Jari; Xhaard, Henri
  Journal of Chemical Information and Modeling (2017), 57 (3), 499-516CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
  We developed a computational workflow to mine the Protein Data Bank (PDB) for isosteric replacements that exist in different binding site environments but have not necessarily been identified and exploited in compd. design. Taking phosphate groups as examples, the workflow was used to construct 157 datasets, each composed of a ref. protein complexed with AMP, ADP, ATP, or pyrophosphate as well other ligands. Phosphate binding sites appeared to have a high hydration content and large size, resulting in U-shaped bioactive conformations recurrently found across unrelated protein families. A total of 16,413 replacements were extd., filtered for a significant structural overlap on phosphate groups, and sorted according to their SMILES codes. In addn. to the classical isosteres of phosphate, such as carboxylate, sulfone or sulfonamide, unexpected replacements that did not conserve charge or polarity, such as aryl, aliph., or pos. charged groups, were found.
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212. 212
  Dufresne, C.; Roy, P.; Wang, Z.; Asante-Appiah, E.; Cromlish, W.; Boie, Y.; Forghani, F.; Desmarais, S.; Wang, Q.; Skorey, K.; Waddleton, D.; Ramachandran, C.; Kennedy, B. P.; Xu, L.; Gordon, R.; Chan, C. C.; Leblanc, Y. The development of potent non-peptidic PTP-1B inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 1039– 1042, DOI: 10.1016/j.bmcl.2003.11.048
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  Bahta, M.; Lountos, G. T.; Dyas, B.; Kim, S.-E.; Ulrich, R. G.; Waugh, D. S.; Burke, T. R., Jr. Utilization of nitrophenylphosphates and oxime-based ligation for the development of nanomolar affinity inhibitors of the Yersinia pestis outer protein H (YopH) phosphatase. J. Med. Chem. 2011, 54, 2933– 2943, DOI: 10.1021/jm200022g
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  Morlacchi, P.; Mandal, P. K.; McMurray, J. S. Synthesis and in vitro evaluation of a peptidomimetic inhibitor targeting the Src homology 2 (SH2) domain of STAT6. ACS Med. Chem. Lett. 2014, 5, 69– 72, DOI: 10.1021/ml4003919
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  Hakogi, T.; Yamamoto, T.; Fujii, S.; Ikeda, K.; Katsumura, S. Synthesis of sphingomyelin difluoromethylene analogue. Tetrahedron Lett. 2006, 47, 2627– 2630, DOI: 10.1016/j.tetlet.2006.02.018
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  Synthesis of sphingomyelin difluoromethylene analog
  Hakogi, Toshikazu; Yamamoto, Tetsuya; Fujii, Shinobu; Ikeda, Kiyoshi; Katsumura, Shigeo
  Tetrahedron Letters (2006), 47 (15), 2627-2630CODEN: TELEAY; ISSN:0040-4039. (Elsevier B.V.)
  As a new sphingomyelinase inhibitor, a novel sphingomyelin CF2 analog was designed and synthesized. One key step of this synthesis is the very mild hydrolysis of the oxazolidinone ring of methylphosphonate I, a suitable intermediate for the introduction of a di-Et difluoro-methylphosphonate group, by utilizing the characteristic electron withdrawing nature of the group at the oxazolidinone ring in an alc. solvent to produce the corresponding carbonate attaching at the secondary hydroxy group. The synthesized CF2 analog inactivated toward B. cereus sphingomyelinase with nearly the same attitude as the nitrogen analog that we previously reported.
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  (a) Lapierre, J.; Ahmed, V.; Chen, M.-J.; Ispahany, M.; Guillemette, J. G.; Taylor, S. D. The difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 151– 155, DOI: 10.1016/j.bmcl.2003.09.089
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  The difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitors
  Lapierre, Jennifer; Ahmed, Vanessa; Chen, Mei-Jin; Ispahany, Mehdi; Guillemette, J. Guy; Taylor, Scott D.
  Bioorganic & Medicinal Chemistry Letters (2004), 14 (1), 151-155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)
  Several estrone sulfate and estradiol sulfate analogs, in which the sulfate group was replaced with an α,α-difluoromethylenesulfonate group or an α,α-difluoromethylenetetrazole group, were examd. as inhibitors of steroid sulfatase (STS). These compds. were 4.5-10.5 times more potent than their non-fluorinated analogs. Moreover, the presence of the fluorines changed the mode of inhibition from mixed to competitive. The inhibitor bearing the α,α-difluoromethylenetetrazole group exhibited an affinity for STS approaching that of the natural STS substrate, estrone sulfate. Possible reasons for the enhanced affinity of the fluorinated compds. compared to their non-fluorinated counterparts are discussed.
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  Liu, Yong; Ahmed, Vanessa; Hill, Bryan; Taylor, Scott D.
  Organic & Biomolecular Chemistry (2005), 3 (18), 3329-3335CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  Steroid sulfatase (STS) catalyzes the hydrolysis of steroidal sulfates such as estrone sulfate (ES1) and is considered to be an attractive target in the treatment of steroid dependent cancers. A non-hydrolyzable estrone sulfate (ES1) analog bearing an α,α-difluorosulfonamide moiety at the 3-position on the A-ring, I, was synthesized. Key to the success of this synthesis was the first use of the allyl group as a sulfonamide protecting group. The pKa of this ES1 mimic in 0.1 M bis-tris propane, 10% DMSO was detd. to be 8.05 using 19F NMR. I is a reversible inhibitor with a Ki similar to that of its sulfonate analog at pH 7.0. It is more potent than its nonfluorinated sulfonamide analog and, its inhibitory potency increases with increasing pH, a trend opposite to that of other STS inhibitors. Possible reasons for this are presented.
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  (a) Maltais, R.; Poirier, D. Steroid sulfatase inhibitors: a review covering the promising 2000–2010 decade. Steroids 2011, 76, 929– 948, DOI: 10.1016/j.steroids.2011.03.010
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  Journal of Steroid Biochemistry and Molecular Biology (2013), 137 (), 183-198CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)
  A review. Sulfated steroids function as a storage reservoir of biol. active steroid hormones. The sulfated steroids themselves are biol. inactive and only become active in vivo when they are converted into their desulfated (unconjugated) form by the enzyme steroid sulfatase (STS). Inhibitors of STS are considered to be potential therapeutics for the treatment of steroid-dependent cancers such as breast, prostate and endometrial cancer. The present review summarizes steroid derivs. as inhibitors of STS covering the literature from the early years of STS inhibitor development to Oct. of 2012. A brief discussion of the function, structure and mechanism of STS and its role in estrogen receptor-pos. (ER+) hormone-dependent breast cancer is also presented.This article is part of a Special Issue entitled "Synthesis and biol. testing of steroid derivs. as inhibitors".
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  Kotoris, C. K.; Chen, M.-J.; Taylor, S. D. Novel phosphate mimetics for the design of non-peptidyl inhibitors of protein tyrosine phosphatases. Bioorg. Med. Chem. Lett. 1998, 8, 3275– 3280, DOI: 10.1016/S0960-894X(98)00598-8
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  Lomelino, C.; McKenna, R. Carbonic anhydrase inhibitors: a review on the progress of patent literature (2011–2016). Expert Opin. Ther. Pat. 2016, 26, 947– 956, DOI: 10.1080/13543776.2016.1203904
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  Lomelino, Carrie; McKenna, Robert
  Expert Opinion on Therapeutic Patents (2016), 26 (8), 947-956CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
  Introduction: A large area of carbonic anhydrase (CA) research focuses on the inhibition of human CA IX and CA XII, as these isoforms have been designated as biomarkers and therapeutic targets for various cancer types. Areas covered: Recently, the majority of CA inhibitor (CAI) patents cover compd. design, synthesis, and delivery methods for the treatment of glaucoma and cancer. The anal. of included patents highlights the need for isoform specific inhibitors. This review covers the patents of medically relevant carbonic anhydrase inhibitors between 2011-2016. Expert opinion: The improvement of structure-based drug design methods and access to the crystal structures of human CA isoforms have improved inhibitor development. This progress can be obsd. in relation to the selective inhibition of CA IX for cancer treatments, with one inhibitor in clin. trials. However, the design of nonclassical CAIs is essential to further improve isoform specificity and prevent sulfur allergies.
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  Blackburn, G. M.; Türkmen, H. Synthesis of α-fluoro- and α,α-difluoro-benzenemethanesulfonamides: new inhibitors of carbonic anhydrase. Org. Biomol. Chem. 2005, 3, 225– 226, DOI: 10.1039/B417327A
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  Naim, M. J.; Alam, O.; Alam, M. J.; Alam, P.; Shrivastava, N. A review on pharmacological profile of morpholine derivatives. Int. J. Pharmacol. Pharm. Sci. 2015, 3, 40– 51
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  Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059
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  Morgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, Klaus
  ChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
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  Martin, R. E.; Plancq, B.; Gavelle, O.; Wagner, B.; Fischer, H.; Bendels, S.; Müller, K. Remote modulation of amine basicity by a phenylsulfone and a phenylthio group. ChemMedChem 2007, 2, 285– 287, DOI: 10.1002/cmdc.200600265
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  ChemMedChem (2007), 2 (3), 285-287CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A series of Ph sulfones and phenylthioamines was studied with respect to their pKa values in water under std. conditions.
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224. 224
  Geneste, P.; Hugon, I.; Reminiac, C.; Lamaty, G.; Roque, J. P. The pK_a of substituted 4-piperidones. Bull. Soc. Chim. Fr. 1976, 5–6, 845– 846
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  Huang, H.; Hutta, D. A.; Rinker, J. M.; Hu, H.; Parsons, W. H.; Schubert, C.; DesJarlais, R. L.; Crysler, C. S.; Chaikin, M. A.; Donatelli, R. R.; Chen, Y.; Cheng, D.; Zhou, Z.; Yurkow, E.; Manthey, C. L.; Player, M. R. Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors. J. Med. Chem. 2009, 52, 1081– 1099, DOI: 10.1021/jm801406h
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  Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Goldsmith, P.; Haslam, C. P.; Mitchell, W. L.; Nicholson, N. H.; Page, L. W.; Patel, S.; Roomans, S.; Slingsby, B. P.; Swarbrick, M. E. Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB₂ agonists for the treatment of inflammatory pain. Bioorg. Med. Chem. Lett. 2010, 20, 465– 468, DOI: 10.1016/j.bmcl.2009.11.117
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  Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory pain
  Gleave, Robert J.; Beswick, Paul J.; Brown, Andrew J.; Giblin, Gerard M. P.; Goldsmith, Paul; Haslam, Carl P.; Mitchell, William L.; Nicholson, Neville H.; Page, Lee W.; Patel, Sadhana; Roomans, Susan; Slingsby, Brian P.; Swarbrick, Martin E.
  Bioorganic & Medicinal Chemistry Letters (2010), 20 (2), 465-468CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  A series of 3-amino-6-aryl-pyridazines have been identified as CB2 agonists with high efficacy and selectivity against the CB1 receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analog I, a compd. with high potency in an in vivo model of inflammatory pain.
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227. 227
  (a) Sundar, B. G.; Bailey, T. R.; Dunn, D.; Hostetler, G. A.; Chatterjee, S.; Bacon, E. R.; Yue, C.; Schweizer, D.; Aimone, L. D.; Gruner, J. A.; Lyons, J.; Raddatz, R.; Lesur, B. Novel morpholine ketone analogs as potent histamine H₃ receptor inverse agonists with wake activity. Bioorg. Med. Chem. Lett. 2012, 22, 1546– 1549, DOI: 10.1016/j.bmcl.2012.01.004
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  Garton, N. S.; Barker, M. D.; Davis, R. P.; Douault, C.; Hooper-Greenhill, E.; Jones, E.; Lewis, H. D.; Liddle, J.; Lugo, D.; McCleary, S.; Preston, A. G. S.; Ramirez-Molina, C.; Neu, M.; Shipley, T. J.; Somers, D. O.; Watson, R. J.; Wilson, D. M. Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 4606– 4612, DOI: 10.1016/j.bmcl.2016.08.070
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  Ahmad, S.; Washburn, W. N.; Hernandez, A. S.; Bisaha, S.; Ngu, K.; Wang, W.; Pelleymounter, M. A.; Longhi, D.; Flynn, N.; Azzara, A. V.; Rohrbach, K.; Devenny, J.; Rooney, S.; Thomas, M.; Glick, S.; Godonis, H.; Harvey, S.; Zhang, H.; Gemzik, B.; Janovitz, E. B.; Huang, C.; Zhang, L.; Robl, J. A.; Murphy, B. J. Synthesis and antiobesity properties of 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): a highly efficacious melanin concentrating hormone receptor 1 (MCHR1) inhibitor. J. Med. Chem. 2016, 59, 8848– 8858, DOI: 10.1021/acs.jmedchem.6b00676
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  (a) Deliencourt-Godefroy, G.; Lopes, L. Family of Aryl, Heteroaryl, O-Aryl and O-Heteroaryl Carbasugars. World Patent Application WO 2012/160218, Nov. 29, 2012.
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  (a) Berry, C. B.; Bubser, M.; Jones, C. K.; Hayes, J. P.; Wepy, J. A.; Locuson, C. W.; Daniels, J. S.; Lindsley, C. W.; Hopkins, C. R. Discovery and characterization of ML398, a potent and selective antagonist of the D₄ receptor with in vivo activity. ACS Med. Chem. Lett. 2014, 5, 1060– 1064, DOI: 10.1021/ml500267c
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  (b) Witt, J. O.; McCollum, A. L.; Hurtado, M. A.; Huseman, E. D.; Jeffries, D. E.; Temple, K. J.; Plumley, H. C.; Blobaum, A. L.; Lindsley, C. W.; Hopkins, C. R. Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D₄R) antagonists. Bioorg. Med. Chem. Lett. 2016, 26, 2481– 2488, DOI: 10.1016/j.bmcl.2016.03.102
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  Saurat, T.; Buron, F.; Rodrigues, N.; de Tauzia, M.-L.; Colliandre, L.; Bourg, S.; Bonnet, P.; Guillaumet, G.; Akssira, M.; Corlu, A.; Guillouzo, C.; Berthier, P.; Rio, P.; Jourdan, M.-L.; Bénédetti, H.; Routier, S. Design, synthesis, and biological activity of pyridopyrimidine scaffolds as novel PI3K/mTOR dual inhibitors. J. Med. Chem. 2014, 57, 613– 631, DOI: 10.1021/jm401138v
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  Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Direct synthesis of fluorinated heteroarylether bioisosteres. Angew. Chem., Int. Ed. 2013, 52, 3949– 3952, DOI: 10.1002/anie.201300763
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  Direct Synthesis of Fluorinated Heteroarylether Bioisosteres
  Zhou, Qianghui; Ruffoni, Alessandro; Gianatassio, Ryan; Fujiwara, Yuta; Sella, Eran; Shabat, Doron; Baran, Phil S.
  Angewandte Chemie, International Edition (2013), 52 (14), 3949-3952CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A modular synthesis of reagents (e.g. sodium 1,1-difluoroethylsulfinate) that can be used for direct incorporation of 1,1-difluoroalkyl groups onto various heterocycles is reported. The scope and generality of the incorporation of difluoroalkyl groups is exemplified with the 1,1-difluoroethyl group, and a proof of principle is shown for a general synthesis of fluorinated heteroaryl ether bioisosteres.
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234. 234
  Xue, F.; Li, H.; Delker, S. L.; Fang, J.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Potent, Highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase. J. Am. Chem. Soc. 2010, 132, 14229– 14238, DOI: 10.1021/ja106175q
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  Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase
  Xue, Fengtian; Li, Huiying; Delker, Silvia L.; Fang, Jianguo; Martasek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.
  Journal of the American Chemical Society (2010), 132 (40), 14229-14238CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compds., e.g., I, contg. a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compds., (S,S) vs. (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF2 moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compds. with monocationic character under physiol. pH conditions. Biol. evaluations have led to a nNOS inhibitor with a Ki of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calcns. indicated that the low pKa NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compd. to the parent mol. shows 22% for the difluorinated compd. vs. essentially no oral bioavailability for the parent compd. This indicates that the goal of this research to make compds. with only one protonated nitrogen atom at physiol. pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.
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235. 235
  Anderson, M. O.; Zhang, J.; Liu, Y.; Yao, C.; Phuan, P.-W.; Verkman, A. S. Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B. J. Med. Chem. 2012, 55, 5942– 5950, DOI: 10.1021/jm300491y
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  Nanomolar Potency and Metabolically Stable Inhibitors of Kidney Urea Transporter UT-B
  Anderson, Marc O.; Zhang, Jicheng; Liu, Yan; Yao, Chenjuan; Phuan, Puay-Wah; Verkman, A. S.
  Journal of Medicinal Chemistry (2012), 55 (12), 5942-5950CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Urea transporters, which include UT-B in kidney microvessels, are potential targets for development of drugs with a novel diuretic ('urearetic') mechanism. We recently identified, by high-throughput screening, a triazolothienopyrimidine UT-B inhibitor, 1, that selectively and reversibly inhibited urea transport with IC50 = 25.1 nM and reduced urinary concn. in mice (Yao et al. J. Am. Soc. Nephrol., in press). Here, we analyzed com. available analogs of (I) to establish a structure-activity series and synthesized a targeted library of 11 analogs to identify potent, metabolically stable UT-B inhibitors. The best compd., {3-[4-(1,1-difluoroethyl)benzenesulfonyl]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}thiophen-2-ylmethylamine, (II), had IC50 of 23 and 15 nM for inhibition of urea transport by mouse and human UT-B, resp., and ∼40-fold improved in vitro metabolic stability compared to I. In mice, II accumulated in kidney and urine and reduced max. urinary concn. Triazolothienopyrimidine may be useful for therapy of diuretic-refractory edema in heart and liver failure.
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236. 236
  Piotrowski, D. W.; Futatsugi, K.; Warmus, J. S.; Orr, S. T.M.; Freeman-Cook, K. D.; Londregan, A. T.; Wei, L.; Jennings, S. M.; Herr, M.; Coffey, S. B.; Jiao, W.; Storer, G.; Hepworth, D.; Wang, J.; Lavergne, S. Y.; Chin, J. E.; Hadcock, J. R.; Brenner, M. B.; Wolford, A. C.; Janssen, A. M.; Roush, N. S.; Buxton, J.; Hinchey, T.; Kalgutkar, A. S.; Sharma, R.; Flynn, D. A. Identification of tetrahydropyrido[4,3-d]pyrimidine amides as a new class of orally bioavailable TGR5 agonists. ACS Med. Chem. Lett. 2013, 4, 63– 68, DOI: 10.1021/ml300277t
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  Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists
  Piotrowski, David W.; Futatsugi, Kentaro; Warmus, Joseph S.; Orr, Suvi T. M.; Freeman-Cook, Kevin D.; Londregan, Allyn T.; Wei, Liuqing; Jennings, Sandra M.; Herr, Michael; Coffey, Steven B.; Jiao, Wenhua; Storer, Gregory; Hepworth, David; Wang, Jian; Lavergne, Sophie Y.; Chin, Janice E.; Hadcock, John R.; Brenner, Martin B.; Wolford, Angela C.; Janssen, Ann M.; Roush, Nicole S.; Buxton, Joanne; Hinchey, Terri; Kalgutkar, Amit S.; Sharma, Raman; Flynn, Declan A.
  ACS Medicinal Chemistry Letters (2013), 4 (1), 63-68CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
  Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biol. target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of I, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that I could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5.
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237. 237
  (a) Xing, L.; Blakemore, D. C.; Narayanan, A.; Unwalla, R.; Lovering, F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. Fluorine in drug design: a case study with fluoroanisoles. ChemMedChem 2015, 10, 715– 726, DOI: 10.1002/cmdc.201402555
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  Fluorine in Drug Design: A Case Study with Fluoroanisoles
  Xing, Li; Blakemore, David C.; Narayanan, Arjun; Unwalla, Ray; Lovering, Frank; Denny, R. Aldrin; Zhou, Huanyu; Bunnage, Mark E.
  ChemMedChem (2015), 10 (4), 715-726CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Anisole and fluoroanisoles display distinct conformational preferences, as evident from a survey of their crystal structures. In addn. to altering the free ligand conformation, various degrees of fluorination have a strong impact on physicochem. and pharmacokinetic properties. Anal. of anisole and fluoroanisole matched mol. pairs in the Pfizer corporate database reveals interesting trends: (1) PhOCF3 increases log D by ∼1 log unit over PhOCH3 compds.; (2) PhOCF3 shows lower passive permeability despite its higher lipophilicity; and (3) PhOCF3 does not appreciably improve metabolic stability over PhOCH3. Emerging from the investigation, difluoroanisole (PhOCF2H) strikes a better balance of properties with noticeable advantages of log D and transcellular permeability over PhOCF3. Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH3 with PhOCF3 is a common tactic to optimize ADME properties, the anal. suggests PhOCF2H may be a more attractive alternative, and greater exploitation of this motif is recommended.
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  (b) Jeschke, P.; Baston, E.; Leroux, F. R. α-Fluorinated ethers as “exotic” entity in medicinal chemistry. Mini-Rev. Med. Chem. 2007, 7, 1027– 1034, DOI: 10.2174/138955707782110150
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  α-Fluorinated ethers as "exotic" entity in medicinal chemistry
  Jeschke, Peter; Baston, Eckhard; Leroux, Frederic R.
  Mini-Reviews in Medicinal Chemistry (2007), 7 (10), 1027-1034CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)
  A review. After nitrogen, fluorine occupies the position of second favorite heteroelement in life science-oriented research. In contrast, the trifluoromethoxy group is still perhaps the least well understood fluorine substituent, although its occurrence has significantly increased in the recent years. Today, significant application areas for trifluoromethoxy substituted pharmaceuticals are in the field of analgesics, anesthetics, cardiovascular drugs, respiratory drugs, psychopharmacol. drugs, neurol. drugs, gastrointestinal drugs and anti-infective therapeutics. The present review will give an overlook of its use in medicinal chem.
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238. 238
  (a) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis. J. Chem. Inf. Model. 2008, 48, 1– 24, DOI: 10.1021/ci7002494
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  238a
  Small molecule conformational preferences derived from crystal structure data. a medicinal chemistry focused analysis
  Brameld, Ken A.; Kuhn, Bernd; Reuter, Deborah C.; Stahl, Martin
  Journal of Chemical Information and Modeling (2008), 48 (1), 1-24CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
  A review. Based on torsion angle distributions of frequently occurring substructures, conformation preferences of druglike mols. are presented, accompanied by a review of the relevant literature. First, the relevance of the Cambridge Structural Database (CSD) for drug design is demonstrated by comparing substructures present in compds. entering clin. trials with those found in the CSD and protein-bound ligands in the Protein Data Bank (PDB). Next, we briefly highlight preferred conformations of elementary acyclic systems, followed by a discussion of sulfonamide conformations. Due to their central role in medicinal chem., we discuss properties of aryl ring substituents in depth, including biaryl systems and systems of two aryl rings connected by two acyclic bonds. For a subset of torsion motifs, we also compare torsion angle histograms derived from CSD structures with those derived from ligands in the PDB. Furthermore, selected properties of some six- and seven-membered ring systems are discussed. The article closes with a section on attractive sulfur-oxygen contacts.
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  238b
  Molecular orbital theory of the electronic structure of organic compounds. XII. Conformations, stabilities, and charge distributions in monosubstituted benzenes
  Hehre, Warren J.; Radom, Leo; Pople, John A.
  Journal of the American Chemical Society (1972), 94 (5), 1496-504CODEN: JACSAT; ISSN:0002-7863.
  Ab initio MO theory with the minimal Slater type orbital obtained by using 3 Gaussian functions basis set is used to study the conformations, stabilities, and charge distributions of 35 monosubstituted benzenes. Mol. conformations are detd. by conjugation effects, although steric interactions cause significant perturbations in some cases. Rotational barriers are a little higher than exptl. values. In the most stable forms of these mols., the Ph group is stabilizing compared with Me. On the other hand, a Ph group oriented perpendicular to the π system of the substituent (e.g., the orthogonal forms of PhNO2 and BzH) is often destabilizing. Calcd. dipole moments are consistently lower than exptl. values, but most exptl. trends are reproduced. Calcd. and exptl. mesomeric moments are in close agreement. Theoretical charge distributions support many of the ideas of classical org. chemistry. In addn. to the transfer of π electrons to or from the substituent into the aromatic ring, polarization of the π electrons within the ring is important. Charge distributions in orthogonal conformations can be strikingly different to those in corresponding planar forms.
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  (c) Anderson, G. M.; Kollman, P. A.; Domelsmith, L. N.; Houk, K. N. Methoxy group nonplanarity in o-dimethoxybenzenes. Simple predictive models for conformations and rotational barriers in alkoxyaromatics. J. Am. Chem. Soc. 1979, 101, 2344– 2352, DOI: 10.1021/ja00503a018
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239. 239
  (a) Kapustin, E. G.; Bzhezovsky, V. M.; Yagupolskii, L. M. Torsion potentials and electronic structure of trifluoromethoxy- and trifluoromethylthiobenzene: an ab initio study. J. Fluorine Chem. 2002, 113, 227– 237, DOI: 10.1016/S0022-1139(01)00556-5
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  Torsion potentials and electronic structure of trifluoromethoxy- and trifluoromethylthiobenzene: an ab initio study
  Kapustin, Evgenij G.; Bzhezovsky, Vladimir M.; Yagupolskii, Lev M.
  Journal of Fluorine Chemistry (2002), 113 (2), 227-237CODEN: JFLCAR; ISSN:0022-1139. (Elsevier Science B.V.)
  Potential functions of internal rotation about the Csp2-X bonds in mols. PhXCF3 (X = O, S) were calcd. at the second-order Moller-Plesset perturbation level of theory with 6-31G(d) basis set. The profile of the potential function and the rotation barrier (ΔE=3.0 kJ/mol) found for PhOCF3 suggest that, depending on exptl. conditions, there can be either free rotation about the Csp2-O bond or the conformational equil. is shifted to the side of the orthogonal form. The rotational barrier for PhSCF3 is 14.7 kJ/mol and the mol. exists in the stable orthogonal conformation. The nature of hybridization, energy and population of lone electron pairs (LPs) on the O and S atoms were considered by using the Natural Bond Orbital (NBO) method. The energy of interactions of the LPs with antibonding π*-orbitals of the arom. moiety were estd. for different conformations. The distribution of electron d. in the mols. was discussed. The results were compared with analogous calcns. on the mols. PhXMe.
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  (b) Horne, D. B.; Bartberger, M. D.; Kaller, M. R.; Monenschein, H.; Zhong, W.; Hitchcock, S. A. Synthesis and conformational analysis of α,α-difluoroalkyl heteroaryl ethers. Tetrahedron Lett. 2009, 50, 5452– 5455, DOI: 10.1016/j.tetlet.2009.07.060
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  Hartz, R. A.; Ahuja, V. T.; Rafalski, M.; Schmitz, W. D.; Brenner, A. B.; Denhart, D. J.; Ditta, J. L.; Deskus, J. A.; Yue, E. W.; Arvanitis, A. G.; Lelas, S.; Li, Y.-W.; Molski, T. F.; Wong, H.; Grace, J. E.; Lentz, K. A.; Li, J.; Lodge, N. J.; Zaczek, R.; Combs, A. P.; Olson, R. E.; Mattson, R. J.; Bronson, J. J.; Macor, J. E. In vitro intrinsic clearance-based optimization of N³-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists. J. Med. Chem. 2009, 52, 4161– 4172, DOI: 10.1021/jm900302q
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  In Vitro Intrinsic Clearance-Based Optimization of N3-Phenylpyrazinones as Corticotropin-Releasing Factor-1 (CRF1) Receptor Antagonists
  Hartz, Richard A.; Ahuja, Vijay T.; Rafalski, Maria; Schmitz, William D.; Brenner, Allison B.; Denhart, Derek J.; Ditta, Jonathan L.; Deskus, Jeffrey A.; Yue, Eddy W.; Arvanitis, Argyrios G.; Lelas, Snjezana; Li, Yu-Wen; Molski, Thaddeus F.; Wong, Harvey; Grace, James E.; Lentz, Kimberley A.; Li, Jianqing; Lodge, Nicholas J.; Zaczek, Robert; Combs, Andrew P.; Olson, Richard E.; Mattson, Ronald J.; Bronson, Joanne J.; Macor, John E.
  Journal of Medicinal Chemistry (2009), 52 (14), 4161-4172CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF1) receptor antagonists. Selected compds., e.g. I, proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, an in vitro intrinsic clearance-based approach is described to the optimization of pyrazinone-based CRF1 receptor antagonists wherein sites of metab. were identified by incubation with human liver microsomes. It was found that the rate of metab. could be decreased by incorporation of appropriate substituents at the primary sites of metab. This led to the discovery of I, a highly potent (IC50 = 1.0 nM) and selective CRF1 receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.
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241. 241
  (a) Massa, M. A.; Spangler, D. P.; Durley, R. C.; Hickory, B. S.; Connolly, D. T.; Witherbee, B.J.; Smith, M. E.; Sikorski, J. A. Novel heteroaryl replacements of aromatic 3-tetrafluoroethoxy substituents in trifluoro-3-(tertiaryamino)-2-propanols as potent inhibitors of cholesteryl ester transfer protein. Bioorg. Med. Chem. Lett. 2001, 11, 1625– 1628, DOI: 10.1016/S0960-894X(01)00244-X
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  (b) Reinhard, E. J.; Wang, J. L.; Durley, R. C.; Fobian, Y. M.; Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.; Norton, M. B.; Promo, M. A.; Tollefson, M. B.; Vernier, W. F.; Connolly, D. T.; Witherbee, B. J.; Melton, M. A.; Regina, K. J.; Smith, M. E.; Sikorski, J. A. Discovery of a simple picomolar inhibitor of cholesteryl ester transfer protein. J. Med. Chem. 2003, 46, 2152– 2168, DOI: 10.1021/jm020528+
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  Discovery of a Simple Picomolar Inhibitor of Cholesteryl Ester Transfer Protein
  Reinhard, Emily J.; Wang, Jane L.; Durley, Richard C.; Fobian, Yvette M.; Grapperhaus, Margaret L.; Hickory, Brian S.; Massa, Mark A.; Norton, Monica B.; Promo, Michele A.; Tollefson, Michael B.; Vernier, William F.; Connolly, Daniel T.; Witherbee, Bryan J.; Melton, Michele A.; Regina, Karen J.; Smith, Mark E.; Sikorski, James A.
  Journal of Medicinal Chemistry (2003), 46 (11), 2152-2168CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead I, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compds. in which the phenoxy group was substituted at the 3, 4, or 5 positions. In general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency relative to I, while analogs contg. electron-donating or hydrogen bond accepting groups exhibited lower potency. Compds. with polar or strong electron-withdrawing groups also displayed lower potency. Replacement of the phenoxy ring in I with either simple aliph. or cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better compds., a representative series was prepd. as the chirally pure R(+) enantiomers, and from these, the 4-chloro-3-ethylphenoxy analog was identified as a potent inhibitor of CETP activity in buffer (IC50 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and biochem. characterization of the 4-chloro-3-ethylphenoxy analog are reported along with its preliminary pharmacol. assessment in animals.
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  (c) Mantlo, N. B.; Escribano, A. Update on the discovery and development of cholesteryl ester transfer protein inhibitors for reducing residual cardiovascular risk. J. Med. Chem. 2014, 57, 1– 17, DOI: 10.1021/jm400574e
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  Update on the Discovery and Development of Cholesteryl Ester Transfer Protein Inhibitors for Reducing Residual Cardiovascular Risk
  Mantlo, Nathan B.; Escribano, Ana
  Journal of Medicinal Chemistry (2014), 57 (1), 1-17CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester and triglycerides between plasma lipoprotein particles HDL and LDL/VLDL, resulting in equilibration between these lipoprotein fractions. Therapy that modulates HDL metab. to increase HDL-c levels could be an effective strategy to reduce residual cardiovascular risk since it is estd. that for each mg/dL increase in plasma HDL cholesterol, there could be a 2-3% decrease in cardiovascular risk. Modification of the lipoprotein profile by CETP inhibitors is promising, but the beneficial effect of reducing coronary heart disease risk has not yet been proven. To date, four CETP inhibitors have advanced to phase 3 cardiovascular outcome clin. trials, and two have been terminated for off-target adverse effects and lack of efficacy. This perspective will summarize recent events, new research developments, and the discovery of new classes of CETP inhibitors.
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242. 242
  (a) Heinrich, T.; Böttcher, H.; Gericke, R.; Bartoszyk, G. D.; Anzali, S.; Seyfried, C. A.; Greiner, H. E.; van Amsterdam, C. Synthesis and structure-activity relationship in a class of indolebutylpiperazines as dual 5-HT_1A receptor agonists and serotonin reuptake inhibitors. J. Med. Chem. 2004, 47, 4684– 4692, DOI: 10.1021/jm040793q
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  (b) Heinrich, T.; Böttcher, H.; Bartoszyk, G. D.; Schwartz, H.; Anzali, S.; März, J.; Greiner, H. E.; Seyfried, C. A. Bioisosterism of fluorine and cyano as indole substituents. Theoretical, in vitro and in vivo examination. Chimia 2004, 58, 143– 147, DOI: 10.2533/000942904777678118
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  Bioisosterism of fluorine and cyano as indole substituents. Theoretical, in vitro and in vivo examination
  Heinrich, Timo; Boettcher, Henning; Bartoszyk, Gerd D.; Schwartz, Harry; Anzali, Soheila; Maerz, Joachim; Greiner, Hartmut E.; Seyfried, Christoph A.
  Chimia (2004), 58 (3), 143-147CODEN: CHIMAD; ISSN:0009-4293. (Swiss Chemical Society)
  A review. Fluorine substitution modifies structural attributes and often induces unexpected effects. When substituting fluorine with cyano in position 5 of the indole in indole-butyl-amines, the properties of the compds. proved to be very comparable. In vitro target-profile, metab., and in vivo activity in the ultrasonic vocalization test indicate bioisosterism between the two substituents.
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243. 243
  (a) Altomonte, S.; Zanda, M. Synthetic chemistry and biological activity of pentafluorosulphanyl (SF₅) organic molecules. J. Fluorine Chem. 2012, 143, 57– 93, DOI: 10.1016/j.jfluchem.2012.06.030
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  Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules
  Altomonte, Stefano; Zanda, Matteo
  Journal of Fluorine Chemistry (2012), 143 (), 57-93CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
  A review. The pentafluorosulphanyl group (SF5) is a highly stable chem. function which has been attracting a great deal of interest owing to its peculiar chem., structural, physicochem. and biol. properties. Progress in the area of SF5-compds. has been somewhat hindered by the lack of straightforward lab-scale synthetic methods for introducing the SF5-group into org. mols. However, recent synthetic progress, the availability of some SF5-building blocks from com. suppliers and the discovery of interesting properties of SF5-substituted mols. in materials science, biol. and drug discovery are giving new momentum to research in this fascinating area of fluorine chem. Synthesis, reactivity and biol. properties of SF5-substituted org. mols. are herein reviewed with an emphasis on the work published after year 2000.
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  (b) Sowaileh, M. F.; Hazlitt, R. A.; Colby, D. A. Application of the pentafluorosulfanyl group as a bioisosteric replacement. ChemMedChem 2017, 12, 1481– 1490, DOI: 10.1002/cmdc.201700356
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  Application of the Pentafluorosulfanyl Group as a Bioisosteric Replacement
  Sowaileh, Munia F.; Hazlitt, Robert A.; Colby, David A.
  ChemMedChem (2017), 12 (18), 1481-1490CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The success of fluorinated mols. in drug design has led medicinal chemists to search for new fluorine-contg. substituents. A major recently developed group is the pentafluorosulfanyl group. This group is stable under physiol. conditions and displays unique phys. and chem. properties. There are currently few synthetic methods to install the SF5 group, yet efforts to integrate this group into lead optimization continue unabated. Typically, the SF5 group has been used as a replacement for trifluoromethyl, tert-Bu, halogen, or nitro groups. In this review, the use of the SF5 group as a bioisosteric replacement for each of these three functionalities is compared and contrasted across various groups of biol. active mols. The organization and presentation of these data should be instructive to medicinal chemists considering to design synthetic strategies to access SF5-substituted mols.
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  (a) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.; Lien, E. J. Aromatic substituent constants for structure-activity correlations. J. Med. Chem. 1973, 16, 1207– 1216, DOI: 10.1021/jm00269a003
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  Aromatic substituent constants for structure-activity correlations
  Hansch, Corwin; Leo, Albert; Unger, Stefan H.; Kim, Ki Hwai; Nikaitani, Donald; Lien, Eric J.
  Journal of Medicinal Chemistry (1973), 16 (11), 1207-16CODEN: JMCMAR; ISSN:0022-2623.
  The arom. substituent consts. π (lipophilic), σm and σp (electronic), and molar refractivity (steric) were collected from the literature for 236 substituents, including 128 π values and 191 values for which both σm and σp were found. The field and resonance electronic properties of C. G. Swain and E. C. Lupton (1968) were calcd. for these 191 substituents by a corrected procedure and were essentially orthogonal. The mutual correlation of σm and σp was high.
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  A survey of Hammett substituent constants and resonance and field parameters
  Hansch, Corwin; Leo, A.; Taft, R. W.
  Chemical Reviews (Washington, DC, United States) (1991), 91 (2), 165-95CODEN: CHREAY; ISSN:0009-2665.
  Included in this review is an anal. of newer methods which can supplant this classic procedure for detn. of the title consts., 283 refs.
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  Du, J.; Hua, G.; Beier, P.; Slawin, A. M. Z.; Woollins, J. D. Single crystal X-ray structural features of aromatic compounds having a pentafluorosulfuranyl (SF₅) functional group. Struct. Chem. 2017, 28, 723– 733, DOI: 10.1007/s11224-016-0854-2
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  Single crystal X-ray structural features of aromatic compounds having a pentafluorosulfuranyl (SF5) functional group
  Du, Junyi; Hua, Guoxiong; Beier, Peter; Slawin, Alexandra M. Z.; Woollins, J. Derek
  Structural Chemistry (2017), 28 (3), 723-733CODEN: STCHES; ISSN:1040-0400. (Springer)
  Nine pentafluorosulfuranyl (SF5)-contg. arom. compds. have been characterized crystallog. The SF5 group has an umbrella geometry, and the sulfur atom in the SF5 group is in an approx. octahedral coordination environment. All S-F bond lengths [1.572(3)-1.618(3) Å] are very similar, and the C-S-Fax bond angles [178.94(14)-180°] are very close to each other. The angle of two adjacent Feq is approx. 90°. The intramol. and intermol. interactions such as Caryl-H···Feq, Caryl-H···O/N/F/Cl interactions, and π-stacking interactions play a very important role in their three-dimensional packing frameworks.
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246. 246
  Rouxel, C.; Le Droumaguet, C.; Macé, Y.; Clift, S.; Mongin, O.; Magnier, E.; Blanchard-Desce, M. Octupolar derivatives functionalized with superacceptor peripheral groups: synthesis and evaluation of the electron-withdrawing ability of potent unusual groups. Chem. - Eur. J. 2012, 18, 12487– 12497, DOI: 10.1002/chem.201103460
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  Octupolar Derivatives Functionalized with Superacceptor Peripheral Groups: Synthesis and Evaluation of the Electron-Withdrawing Ability of Potent Unusual Groups
  Rouxel, Cedric; Le Droumaguet, Celine; Mace, Yohan; Clift, Sophie; Mongin, Olivier; Magnier, Emmanuel; Blanchard-Desce, Mireille
  Chemistry - A European Journal (2012), 18 (39), 12487-12497, S12487/1-S12487/6CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Novel tripodal derivs. with a triphenylamine core and that bear "superacidifiers" (i.e., fluorinated sulfoximinyl blocks) or novel sulfiliminyl moieties as peripheral groups were synthesized. These new chromophores show strong absorption in the near-UV region and emission in the visible region. The fluorinated sulfoximinyl moieties were found to behave as potent auxochromic and electron-withdrawing (EW) groups, thus leading to red shifted absorption and emission. These moieties promote a core-to-periphery intramol. charge transfer (ctp-ICT) transition, the energy of which was found to be correlated to their EW strength. In this study, we provide evidence of a linear correlation between the Hammett const. (σp) values and the electronic gap between the ground and first excited state of the three-branched derivs. This in turn was used to derive σp values of fluorinated sulfoximinyl moieties. These EWGs show unprecedentedly high σp values, up to 1.45 relative to 0.8 for NO2. Also, by using this method, the sulfiliminyl moiety was shown to exhibit similar EW strength as NO2, while promoting improved transparency and soly. Finally, the superior EW strength of the fluorinated sulfoximine peripheral moieties was shown to induce significant enhancement of the two-photon absorption responses in the red near-IR region of the three-branched derivs. relative to similar octupoles that bear more usual strong EW groups. These characteristics (improved nonlinear responses or transparency) open new routes for the design of nonlinear optical (NLO) chromophores for optical limiting or electro-optical modulation. Such building blocks could also be of interest for optoelectronic applications, including the development of solar cells.
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  (a) Bowden, R. D.; Comina, P. J.; Greenhall, M. P.; Kariuki, B. M.; Loveday, A.; Philp, D. A new method for the synthesis of aromatic sulfurpentafluorides and studies of the stability of the sulfurpentafluoride group in common synthetic transformations. Tetrahedron 2000, 56, 3399– 3408, DOI: 10.1016/S0040-4020(00)00184-8
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  (b) Savoie, P. R.; Welch, J. T. Preparation and utility of organic pentafluorosulfanyl-containing compounds. Chem. Rev. 2015, 115, 1130– 1190, DOI: 10.1021/cr500336u
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  Preparation and utility of organic pentafluorosulfanyl-containing compounds
  Savoie, Paul R.; Welch, John T.
  Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 1130-1190CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review on prepn. of pentafluorosulfanyl-contg. compds. and their use in a variety of synthetic org. reactions.
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Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

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Abstract

Introduction

Key Properties of Fluorine of Relevance to Bioisostere Design

Fluorine as a Bioisostere of the Hydrogen Atom in Alkyl Moieties

Developability Aspects Associated with Fluorination and the Size of the CF3 Moiety

Fluorination as an Approach to Reducing Metabolism

Figure 1

Figure 2

Scheme 1

Metabolic Activation of Fluoro-alkyl Derivatives

Scheme 2

2,2-Difluoro-1,3-benzodioxole Derivatives

Scheme 3

Fluorination of Alkyl Groups and Conformational Effects

Fluorine for Hydrogen in Alkyl Groups Proximal to Amines

Figure 3

Figure 4

Fluorine for Hydrogen in Alkyl Groups Proximal to Amides

Figure 5

Figure 6

Fluorine for Hydrogen in Alkyl Groups Proximal to Fluorine

Figure 7

Replacing Hydrogen by Fluorine in Aromatic Rings

Aryl Fluoride Derivatives and Metabolism

Scheme 4

Aryl Fluorides: Membrane Permeability and P-gp Recognition

Figure 8

Aryl Fluorides and Conformation of Proximal Substituents

Aryl Fluorination and Solubility

Fluorine Mimicry with Nitrogen-Based Lone Pairs of Electrons

Aromatic Fluoride and Azine Mimesis

Figure 9

Figure 10

Figure 11

Nitrogen Lone Pair Mimesis by an Alkyl Fluoride

Figure 12

Flourination and Potency

Multipolar and Hydrogen Interactions of Fluorine with Proteins

Figure 13

Figure 14

Figure 15

The CF3 Moiety and Tetrel Bonding

Figure 16

Figure 17

Figure 18

Figure 19

Fluorine and the Modulation of the Basicity of Amines

N-CF3 Derivatives

Fluorine and Carbonyl Bioisosterism

sp3 C–F as a C═O Bioisostere

Fluoro Alkenes and Aromatic Fluorides as C═O Bioisosteres

Figure 20

Examples of Fluorinated Alkenes As Amide Bioisosteres

Aromatic Fluorides as C═O Bioisosteres

Figure 21

Figure 22

Figure 23

Figure 24

Alkenyl Fluoride as an Enol Mimetic

Scheme 5

Scheme 6

The 1,1-Difluoro Alkene Moiety as a C═O Bioisostere

Figure 25

Scheme 7

Scheme 8

The CF2 Moiety as a C═O Bioisostere

Fluorinated Motifs as Amide, Sulfonamide, and Urea Mimetics

Trifluoroethylamine and Difluoroethylamine Derivatives

Figure 26

Figure 27

RCF2CH2NHR′ as a Bioisostere of RSO2NHR′

Fluorinated Amines and Mimesis of Imide-like Motifs

N-CH(CF3)2 as a Sulfone Bioisostere

Fluorinated Motifs and Urea Bioisosterism

Developability Aspects Associated with Fluorination and the Size of the CF₃ Moiety

The CF₃ Moiety and Tetrel Bonding

N-CF₃ Derivatives

sp³ C–F as a C═O Bioisostere

The CF₂ Moiety as a C═O Bioisostere

RCF₂CH₂NHR′ as a Bioisostere of RSO₂NHR′

N-CH(CF₃)₂ as a Sulfone Bioisostere

CF₂ as a Bioisostere of an Oxygen Atom

CF₂ and Phosphate/Pyrophosphate Mimicry

CF₂ as an Oxygen Bioisostere in Sulfonic Acids and Sulfonamides

CF₂ as an Oxygen Bioisostere in Heterocycles

ArCF₂CH₃ and ArOR Bioisosterism

The SF₅ Moiety